This international phase III, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of lenalidomide in RBC transfusion-dependent patients with International Prognostic ...Scoring System lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents.
In total, 239 patients were randomly assigned (2:1) to treatment with lenalidomide (n = 160) or placebo (n = 79) once per day (on 28-day cycles). The primary end point was the rate of RBC transfusion independence (TI) ≥ 8 weeks. Secondary end points were RBC-TI ≥ 24 weeks, duration of RBC-TI, erythroid response, health-related quality of life (HRQoL), and safety.
RBC-TI ≥ 8 weeks was achieved in 26.9% and 2.5% of patients in the lenalidomide and placebo groups, respectively (P < .001). Ninety percent of patients achieving RBC-TI responded within 16 weeks of treatment. Median duration of RBC-TI with lenalidomide was 30.9 weeks (95% CI, 20.7 to 59.1). Transfusion reduction of ≥ 4 units packed RBCs, on the basis of a 112-day assessment, was 21.8% in the lenalidomide group and 0% in the placebo group. Higher response rates were observed in patients with lower baseline endogenous erythropoietin ≤ 500 mU/mL (34.0% v 15.5% for > 500 mU/mL). At week 12, mean changes in HRQoL scores from baseline did not differ significantly between treatment groups, which suggests that lenalidomide did not adversely affect HRQoL. Achievement of RBC-TI ≥ 8 weeks was associated with significant improvements in HRQoL (P < .01). The most common treatment-emergent adverse events were neutropenia and thrombocytopenia.
Lenalidomide yields sustained RBC-TI in 26.9% of RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. Response to lenalidomide was associated with improved HRQoL. Treatment-emergent adverse event data were consistent with the known safety profile of lenalidomide.
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Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red ...blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q).
Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg.
Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia 49.3% vs 73.7% for non-del(5q) vs del(5q), respectively, thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia 45.2% vs 72.0% for non-del(5q) and del(5q), respectively, thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%.
Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies.
Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable.
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Almeida:Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.
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Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), ...LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs.
Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs pRBCs/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin EPO > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262.
Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed.
Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population.
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Santini:Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.
Background: Anemia represents a challenge in the management of patients with myelofibrosis (MF); at least a third of patients with MF are reported to have hemoglobin levels <10 g/dL and approximately ...25% of these patients are red blood cell (RBC) transfusion-dependent at the time of diagnosis. Elevated serum hepcidin levels have been shown to be associated with anemia, increased requirement for RBC transfusions, and reduced overall survival in patients with MF. Hepcidin levels are regulated by the serine/threonine kinase, activin receptor-like kinase 2 (ALK2); in preclinical studies, knockdown or loss of ALK2 leading to decreased hepcidin production results in elevated serum iron levels. INCB000928 is a potent, orally bioavailable, and highly selective small molecule inhibitor of ALK2, and may represent a potential therapeutic strategy for hepcidin-induced anemia. INCB 00928-104 is designed to evaluate the safety and tolerability of INCB000928 as monotherapy or in combination with ruxolitinib in patients with anemia due to MF.
Methods: INCB 00928-104 (NCT04455841) is a phase 1/2, open-label, multicenter, dose-escalation and -expansion study assessing INCB000928 alone (treatment group A TGA) or in combination with ruxolitinib (treatment group B TGB), in patients with MF who are transfusion-dependent or present with symptomatic anemia (Figure). For TGA, patients must have been intolerant, resistant, refractory, or lost response to prior therapy (≥12 weeks) with Janus kinase inhibitors and have a risk category of intermediate-2 or high according to the Dynamic International Prognostic Scoring System (DIPSS); for TGB, patients must have been on a therapeutic and stable regimen of ruxolitinib for ≥12 consecutive weeks prior to first dose of study treatment and have a DIPSS risk category of intermediate-1 or -2, or high. To be eligible patients must be ≥18 years of age, have an Eastern Cooperative Oncology Group performance status 0-1 for the dose-escalation stages or 0-2 for the dose-expansion stage, have life expectancy > 6 months, and have histologically confirmed primary or secondary (post-polycythemia vera, post-essential thrombocythemia) MF. Patients are ineligible if they have any other hematologic malignancy; have undergone any prior allogeneic or autologous stem cell transplantation; have undergone major surgery within 28 days of first dose of study drug; or have received prior disease-directed therapy within 5 half-lives or 28 days before first dose of study drug.
In Part 1 (dose escalation) of the study, patients will be enrolled into TGA or TGB. INCB000928 monotherapy will be administered orally at a starting dose of 50 mg/day in TGA (28-day cycles). The dose-escalation stage will use a Bayesian optimal interval design to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), with dose increases not exceeding 100% (2-fold) until a treatment-related toxicity Grade ≥2 is observed. Dose escalation in TGB will start 2 dose levels below the maximum evaluated dose determined to be safe and tolerable in TGA; patients in TGB will receive INCB000928 in combination with ruxolitinib. In each treatment group in Part 1, ≤24 patients will be treated in the dose-escalation stage. In Part 2 (dose expansion), the RDE in TGB will be evaluated in combination with ruxolitinib in approximately 25 patients. Patients will receive treatment for up to 12 months, and treatment may continue if patients are deriving clinical benefit and have no evidence of progressive disease.
The primary study objective is to determine the safety and tolerability of INCB000928 monotherapy or in combination with ruxolitinib, and to identify dose-limiting toxicities, MTD, and RDE for TGB). Secondary objectives are: to determine the efficacy of INCB000928 monotherapy or in combination with ruxolitinib (assessed by anemia response, duration of anemia response, mean change from baseline in hemoglobin, and rate of RBC transfusion through week 24 and 48); to evaluate pharmacokinetics of INCB000928; and to evaluate the effect of INCB000928 as monotherapy or in combination with ruxolitinib on hepcidin level, and other measures of iron homeostasis and erythropoiesis.
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Oh:Incyte Corporation: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Kartos Therapeutics: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; Constellation: Consultancy; CTI Biopharma: Consultancy. Gotlib:Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding. Mohan:Incyte Corporation: Research Funding; Novartis: Research Funding. Ali:Incyte Corporation: Consultancy. Asatiani:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Seguy:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zhou:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding.
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Background: Elevated levels of the iron regulator hepcidin can cause functional iron deficiency anemia; hepcidin dysregulation is central to anemia of chronic inflammation observed in several ...malignancies such as MF. ALK2 (ie, ACVR1) contributes to MF-associated anemia via hepcidin upregulation. We evaluated the safety and activity of zilurgisertib, a selective, oral ALK2 inhibitor, in pts with anemia due to MF. Methods: The ongoing open-label, multicenter, phase 1/2 dose-escalation/expansion INCB 00928-104 study (NCT04455841) is evaluating zilurgisertib alone (treatment group A TGA) or with RUX (treatment group B TGB). Eligible pts are ≥18 years old with primary/secondary MF of intermediate (Int)-1 (TGB only) or Int-2/high-risk (TGA and TGB) per the Dynamic International Prognostic Scoring System (DIPSS) and are transfusion-dependent or have symptomatic anemia. The primary endpoint is safety and tolerability. Secondary endpoints include efficacy (per anemia response parameters), pharmacokinetics, and pharmacodynamics (eg, hepcidin and iron metabolism parameters). Results: 31 pts were enrolled by data cutoff (30Nov2022), with 20 in TGA (50 mg once daily qd, n = 4; 100 mg qd, n = 4; 200 mg qd, n = 6; 400 mg qd, n = 6) and 11 in TGB (100 mg qd, n = 4; 200 mg qd, n = 5; 400 mg qd, n = 2). Median (range) age was 73 (5384) y for TGA and 77 (6485) y for TGB. 65% of TGA pts had received prior RUX therapy. Overall, 90% of pts had Int-2 risk DIPSS, and the remainder had high-risk DIPSS (1 pt in TGA, 2 in TGB). 60% of pts in TGA and 27% in TGB were transfusion-dependent at the time of enrollment. Median baseline (BL) hemoglobin (Hb) was 7.7 (range, 710) g/dL in TGA and 8.5 (range, 89) g/dL in TGB. BL hepcidin was high in both cohorts (median range: TGA, 171 18535 ng/mL; TGB, 123 7250 ng/mL; normal range, 050 ng/mL). At the time of analysis, dose escalation was ongoing in both treatment groups. No dose-limiting toxicities (DLTs) or study drugrelated serious adverse events (AEs) occurred in either treatment group. Maximum tolerated dose had not been reached at the time of analysis. Treatment-emergent AEs (TEAEs) were mainly low grade. Grade ≥3 TEAEs occurred in 7 pts, with thrombocytopenia the most common (n = 4). Reduction in hepcidin following zilurgisertib dosing was observed in TGA and TGB, with maximal hepcidin reduction at 6 h postdose. Hb increase of > 1.5 g/dL from BL occurred in 3 pts (27%) in TGB and 1 pt (5%) in TGA. Conclusions: Treatment with zilurgisertib monotherapy or in combination with RUX in this patient population was generally well tolerated, with predominantly grade 1/2 TEAEs and no DLTs. Reduced hepcidin levels were observed with both monotherapy and in combination with RUX, and preliminary improvements in anemia were observed, which suggest potential for therapeutic activity. Clinical trial information: NCT04455841 .
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Background: BET proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including MF. INCB057643 is a ...small-molecule BET inhibitor evaluated as monotherapy and in combination with ruxolitinib (RUX) in pts with advanced malignancies in 2 previous phase 1/2 clinical trials. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) evaluates safety and tolerability of INCB057643 (4 mg once daily qd; escalation up to 12 mg qd) in pts aged ≥18 years as (1) monotherapy (part 1) in R/R MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to RUX (part 2) in pts with MF and suboptimal response to RUX. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs). Results: 13 pts have been treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=1; 12 mg, n=2), and 3 pts received 4 mg + RUX in part 2 (overall age range, 50–79 years; men, n=9; study treatment duration range, 15–314 days). 12 pts had MF, and 4 had MDS/MPN. All 6 pts in the 4-mg cohort discontinued treatment (3 for progressive disease PD; MF, n=2; MDS/MPN, n=1); 1 pt with MF in the 12-mg cohort discontinued for thrombocytopenia. The other 9 pts remain on treatment. Thrombocytopenia was the most common treatment-emergent adverse event (TEAE; n=9; Table) and the only TEAE leading to discontinuation (n=3). Grade ≥3 TEAEs occurring in ≥1 pt were thrombocytopenia (n=4), anemia (n=3), and hypokalemia (n=2). There were 8 serious AEs across 4 pts, with only COVID-19 occurring in >1 pt (n=2); all but one (pneumonia) were considered unrelated to study treatment. There were 2 DLTs (thrombocytopenia MDS/MPN pt and hyperbilirubinemia MF pt; both 12-mg cohort) and 2 deaths (both 4-mg cohort due to PD MF, n=1; MDS/MPN, n=1). Conclusions: Treatment with INCB057643 monotherapy (4 and 8 mg qd) and in combination (4 mg qd) with RUX was generally well tolerated in this pt population. The 12-mg qd monotherapy dose was not tolerated and caused 2 DLTs. There were no treatment-related fatal events. Dose finding in part 1 is ongoing with 10 mg qd, after which a recommended phase 2 dose will be declared. Combination dose escalation is also ongoing. Preliminary efficacy including spleen size and symptoms will be available for presentation. Clinical trial information: NCT04279847 . Table: see text
Abstract
Background: Anemia represents a therapeutic challenge in patients with myelofibrosis (MF). ALK2 activation is associated with elevated hepcidin, which may contribute to anemia of chronic ...disease and anemia due to hematologic malignancies, and is associated with increased transfusion rate and reduced overall survival. This phase 1/2, open-label, multicenter, dose-escalation/dose-expansion study will evaluate the safety and tolerability of INCB000928, a potent, highly selective, ALK2 inhibitor, as monotherapy or combined with ruxolitinib in patients with anemia due to MF (INCB 00928-104; NCT04455841). Methods: Patients with histologically confirmed primary/secondary MF presenting with transfusion-dependent or symptomatic anemia will receive oral INCB000928 either alone (treatment group TG A) or combined with ruxolitinib (TGB). In TGA, patients must have intermediate (INT)-2 or high-risk (per Dynamic International Prognostic Scoring System DIPSS) disease that is intolerant, resistant, refractory, or has lost response to prior JAK inhibitor therapy (≥12 weeks). In TGB, patients must have received stable ruxolitinib therapy for ≥12 consecutive weeks before first dose and have INT-1/INT-2, or high-risk disease. Eligibility also requires age ≥18 y, ECOG PS 0-1 (dose-escalation) or 0-2 (dose-expansion), life expectancy >6 months, no other hematologic malignancy, no prior stem cell transplantation, no major surgery within 28 days, and no prior disease-directed therapy within 5 half-lives or 28 days of first dose. In Part 1 (dose escalation), TGA will receive INCB000928 monotherapy starting at 50 mg/day (28-day cycles). Dose-escalation will follow a Bayesian optimal-interval design to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE). Dose increases not exceeding 2-fold will continue until Grade ≥2 treatment-related toxicity occurs. TGB will receive INCB000928 plus ruxolitinib; INCB000928 dose escalation will start 2 dose levels below the highest dose determined to be safe and tolerable in TGA. In Part 2 (dose expansion), the RDE in TGB will be evaluated in combination with ruxolitinib in ~25 patients; treatment will continue for ≤12 months, and may continue if clinically beneficial and no progression occurs. Primary objective is to determine the safety and tolerability of INCB000928 as monotherapy or combined with ruxolitinib. Secondary objectives are to determine the efficacy of INCB000928 as monotherapy or combined with ruxolitinib (anemia response, duration of anemia response, mean change from baseline in hemoglobin, and RBC transfusion rate through weeks 24 and 48); evaluate INCB000928 pharmacokinetics; and evaluate effects of INCB000928 as monotherapy or combined with ruxolitinib on hepcidin levels and other measures of iron homeostasis and erythropoiesis.
Citation Format: Stephen T. Oh, Jean-Jacques Kiladjian, Francesca Palandri, Jason R. Gotlib, Sanjay Mohan, Haris Ali, Ekatherine Asatiani, Francis Seguy, Feng Zhou, Srdan Verstovsek. A Phase 1/2 Study of INCB000928 as Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT216.
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