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.

Ruxolitinib

Tolerability

10.1158/1538-7445.am2021-ct216

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Citations (1)

Effect of Ruxolitinib On the Incidence of Splenectomy in Patients with Myelofibrosis: A Retrospective Analysis of Data From Ruxolitinib Clinical Trials.

Blood (2012)

Srđan Verstovšek Jean‐Jacques Kiladjian Ruben A. Mesa Alessandro M. Vannucchi Jason Gotlib

Ruxolitinib

Myeloproliferative neoplasm

10.1182/blood.v120.21.2847.2847

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Citations (7)

The serum tryptase test: an emerging robust biomarker in clinical hematology

Expert Review of Hematology (2014)

Peter Valent Wolfgang R. Sperr Karl Sotlar Andreas Reiter Cem Akin

During the past few years, a number of molecular markers have been developed in clinical hematology, most of them related to specific gene defects. However, there is also an unmet need to develop novel serologic parameters to improve diagnostics and prognostication in daily practice. Among these, the serum tryptase appears to be a most reliable biomarker of myeloid neoplasms. Elevated tryptase levels are found in subgroups of patients with mastocytosis, myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, chronic myeloid leukemia and chronic eosinophilic leukemia. In these patients, the tryptase level is of diagnostic and/or prognostic significance. In mastocytosis, an elevated tryptase level is a minor criterion of systemic disease and in BCR-ABL1+ chronic myeloid leukemia, elevated tryptase at diagnosis correlates with treatment responses and overall survival. In patients with elevated tryptase, the enzyme also serves as follow-up parameter and can be employed to measure treatment-responses. In the current article, we review and update the perspectives of tryptase and provide recommendations for use of this conventional biomarker in daily practice.

Tryptase

Hematology

Myeloproliferative neoplasm

10.1586/17474086.2014.955008

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Citations (72)

A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM)

Blood (2021)

Jason Gotlib Tracy I. George Michael W. Deininger Tsewang Tashi Vinod Pullarkat

Cutaneous Mastocytosis

10.1182/blood-2021-145928

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Citations (7)

Identification of a Novel MPL Loss of Function Mutation in a Patient with Cyclic Thrombocytopenia and Characterization of This Syndrome

Blood (2016)

Haiyu Zhang Yu Hou Rondeep Brar Bing Zhang Zhenping Chen

Sanger sequencing

10.1182/blood.v128.22.1376.1376

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Citations (4)

POSTER: MPN-524 Reductions in Indolent Systemic Mastocytosis Biomarker Burden With Avapritinib in the Registrational, Double-Blind, Placebo-Controlled PIONEER Trial

Clinical Lymphoma Myeloma & Leukemia (2023)

Jason Gotlib Mariana Castells Hanneke Oude Elberink Frank Siebenhaar Karin Hartmann

10.1016/s2152-2650(23)00661-4

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Citations (0)

Supplementary File 2 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches

Pramod C. Nair Jacob Piehler Denis Tvorogov David M. Ross Angel F. López

<p>JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).</p>

10.1158/2643-3230.23792312.v1

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Farnesyltransferase inhibitor therapy in acute myelogenous leukemia.

PubMed (2005)

Jason Gotlib

Acute myelogenous leukemia (AML) remains a clinical challenge with poor long-term survival. Low remission rates and high treatment-related mortality persist as major obstacles, particularly in older patients. The design of novel agents based on the identification of genetic lesions and aberrant signaling pathways provides opportunity to improve the standard treatment paradigm of intensive cytotoxic chemotherapy. Farnesyltransferase inhibitors (FTIs) show potential to fill this niche. The preclinical concept of farnesyltransferase blockade as a targeted therapy against oncogenic Ras has clearly evolved with the recognition that many proteins involved signaling pathways in tumor cells undergo farnesylation. Phase I/II trials of FTI monotherapy in AML demonstrate encouraging responses and good tolerability. The FTI tipifarnib (R115777, Zarnestra; Johnson & Johnson, Titusville, NJ) has advanced the furthest in clinical trials, with the most promising activity in previously untreated, high-risk AML patients. A major emphasis of current clinical studies has been to analyze potential candidate genes and signaling pathways modified by FTIs in order to identify mechanisms of response and resistance. Preclinical concepts related to the development of FTIs, the rationale for their use in AML, and efficacy and safety results from recent clinical trials are evaluated in this paper.

Farnesyltransferase inhibitor

Tolerability

Farnesyl-diphosphate farnesyltransferase

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Citations (33)

A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis

New England Journal of Medicine (2012)

Srđan Verstovšek Ruben A. Mesa Jason Gotlib Richard S. Levy Vikas Gupta

Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.

Ruxolitinib

Janus kinase inhibitor

Janus kinase 2

10.1056/nejmoa1110557

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Citations (1,881)