Background: Myelofibrosis (MF), which comprises primary MF (PMF), post-polycythemia vera MF (post-PV-MF), and post-essential thrombocythemia MF (post-ET-MF), is a clonal myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, ineffective erythropoiesis, dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. Patients typically have heterogeneous clinical presentation marked by splenomegaly, progressive anemia and constitutional symptoms and are at increased risk of leukemic transformation. Hematopoietic stem cell transplant is the only potentially curative therapy but is associated with high morbidity and mortality. Approved therapies for MF are limited to the Janus kinase inhibitors (JAKi) ruxolitinib and fedratinib which have been shown to reduce spleen volume (≥35% from baseline at week 24) in 32% - 42% of patients and to improve constitutional symptoms, with no clear impact on bone marrow fibrosis. Several studies have shown a correlation between the degree of week 24 spleen response to JAKi treatment and survival outcomes in MF (Vannucchi, et al. Haematologica. 2015; Palandri et al. Leuk Res. 2018), demonstrating the need for novel treatment strategies in patients with a suboptimal response to ruxolitinib treatment.
KRT-232 is a potent, selective, orally available, small molecule drug that binds to MDM2, a key negative regulator of the tumor suppressor protein p53. MDM2 blocks p53 activity via ubiquitination, nuclear export and direct inhibition of transcriptional activity. In MF, somatic driver mutations such as JAK2 V617F are associated with MDM2 overexpression in the circulating CD34+ cells that are a characteristic feature of the disease (Lu, et al. Blood. 2017). The first clinical proof-of-concept study of KRT-232 monotherapy showed promising efficacy and tolerability in patients with MF relapsed or refractory (R/R) to prior JAKi treatment (Al-Ali et al. EHA 2020). It is hypothesized that KRT-232 may deliver synergistic efficacy and disease modification when combined with ruxolitinib by targeting a complementary mechanism that promotes apoptosis in malignant MF clones. Further, by combining ruxolitinib with KRT-232 to inhibit both the aberrant JAK/STAT signaling and the upregulation of MDM2-mediated survival pathways, this combination has the potential to lower the apoptotic threshold of malignant cells that are deprived of growth factor and cytokine support.
Study Design/Methods: KRT-232 in combination with ruxolitinib is being evaluated in an open-label, global, multicenter phase 1b/2 study in patients with MF (PMF/post-PV-MF/post-ET-MF) who have a suboptimal response after ≥18 weeks of ruxolitinib treatment (Figure). Patients aged ≥18 years, on stable dose of ruxolitinib for at least 8 weeks prior to enrollment and with ECOG performance status of 0-2 will be enrolled. Patients with TP53 mutations, spleen response or progressive disease during ruxolitinib treatment per European LeukemiaNet criteria (Tefferi, et al. Blood. 2013), or prior JAKi treatment other than ruxolitinib are excluded. In the phase 1b portion of the study, patients will be randomly assigned to arm 1 (KRT-232 once daily [qd] on days [D] 1-7 of 28-day cycle) or arm 2 (KRT-232 qd on D1-5 of 28-day cycle). KRT-232 will be administered in a 3+3 dose-escalation design with doses starting at KRT-232 120 mg, increasing to 180 mg, followed by 240 mg in combination with the patient's pre-study stable dose of ruxolitinib to determine the maximum tolerated dose (MTD) of KRT-232 + ruxolitinib. The phase 2 portion will evaluate the MTD reached in arm 1 and arm 2 as expansion arms, assessing the safety and efficacy of the combinations to determine a recommended phase 2 dose (RP2D).
The primary end point of the study is to determine the RP2D of KRT-232 + ruxolitinib. Secondary end points include spleen response (≥35% spleen volume reduction from baseline), change in Myelofibrosis Symptom Assessment Form version 4.0 Total Symptom Score, duration of response, spleen size reduction, red blood cell transfusion usage and independence, overall response rate (complete response + partial response), overall survival, progression-free survival, leukemia-free survival, safety/tolerability, and pharmacokinetics. This trial is enrolling at approximately 40 global sites (NCT04485260).
Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Vannucchi:Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mead:Gilead: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Pluta:Janssen-Cilag, Kartos Therapeutics, Iqvia, Roche, Acerta Pharma, Pharmacyclics, BeiGene, Takeda: Research Funding; Celgene, Servier, Takeda, Novartis: Honoraria; Celgene: Other: Travel, Accommodations, Expenses. Qamoos:Kartos Therapeutics: Current Employment, Current equity holder in private company. Uyei:Kartos Therapeutics: Current Employment. Gandhi Laurent:Abbevie, Pfizer, Takeda, Roche: Other: Travel; Roche, Takeda, Iqone, Accord: Consultancy; Roche, Takeda, Accord: Honoraria. Al-Ali:AOP Orphan: Other: travel, accommodations, expenses; Incyte: Research Funding; Pfizer: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Yes, KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a clinical trial that will evaluate the safety and efficacy of KRT-232 + ruxolitinib for patients with myelofibrosis with suboptimal response to ruxolitinib.
Asterisk with author names denotes non-ASH members.