Phase II results from KRT-232, a first-in-class MDM2 inhibitor, for R/R MF failing JAK inhibitor therapy

Janus kinase (JAK) inhibitors (JAKi) are commonly used in patients with myelofibrosis (MF), however, more than half of patients may discontinue treatment within 3 years due to disease progression or intolerance. There is an unmet need for this patient population which has a poor prognosis with a median overall survival of approximately 14 months. Murine double minute 2 (MDM2) is a negative modulator of p53 and is overexpressed in circulating CD34+ cells that are found in increased levels in patients with MF. KRT-232 is a first-in-class, potent, selective, small molecule MDM2 inhibitor that has a potential to target the malignant MF stem and progenitor cells, and is currently being investigated in an ongoing, single-arm, phase IIa-IIb study, KRT-232-101 (NCT03662126) in patients with primary or secondary MF, and who have relapsed and/or refractory (R/R) disease following JAKi treatment. The MPN Hub Steering Committee member, Haifa Kathrin Al-Ali presented the results during the 25th European Hematology Association (EHA) Virtual Congress, and here, we summarize them.¹

Study design^1,2

• A multicenter, global, randomized phase II study with two parts
• Eligibility criteria: Age ≥ 18 years, TP53^WT primary MF (PMF), post-polycythemia vera (PV) MF (post-PV MF) or post-essential thrombocythemia (ET) MF (Post-ET MF), Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and intermediate/high-risk disease based on the Dynamic International Prognostic Scoring System (DIPSS)
• Patients intolerant to JAK inhibitors were excluded
• No mandatory washout period for ruxolitinib was required

• Part A: Two different oral dose (120 mg and 240 mg), and three different dose schedules:

• • Cohort 1: 120 mg once daily between Days 1 to 7, off treatment between Days 8 to 21 (21-day cycle)
  • Cohort 2: 240 mg once daily between Days 1 to 7, off treatment between Days 8 to 21 (21-day cycle)
  • Cohort 3: 240 mg once daily between Days 1 to 7, off treatment between Days 8 to 21 (28-day cycle)

Of note, Cohort 2 has been closed to enrollment due to lack of tolerability, and patients have been transferred to Cohort 3. Another treatment arm (Cohort 4) is in the enrollment phase for a dose schedule of 240 mg once daily between Days 1 to 5, and off treatment between Days 6 to 28 in a 28-day cycle.

• Part B (not started): Treatment with the recommended dose and dosing schedule from Part A
• Endpoints:

• • Primary endpoint: Spleen response rate by a ≥ 35% reduction in spleen volume from baseline at Week 24 on MRI or CT
  • Secondary endpoints: Safety and tolerability, ≥ 50% reduction in total symptom score (TSS) by modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), v2.0

Patient characteristics¹

The total number of patients was 82, and median age was 69 years (range, 33–85). The proportion of patients with ECOG performance status of 0, 1, and 2 was 31%, 51%, and 17%, respectively. The majority of patients (67%) had PMF and the proportion of patients with hemoglobin level below 10 g/dL was 63%. Key patient characteristics among three cohorts are provided in Table 1.

Table 1. Baseline characteristics¹

 Results¹

• Spleen volume reduction (SVR) was observed at all dose levels, however, there was a dose-dependency with best response seen at 240 mg. Of all evaluable patients (N = 25) in Cohort 3 (240 mg, 28-day) SVR ≥ 35% was seen in 16% (n = 4).
• With no mandatory washout period for ruxolitinib, the drug was considered a confounding factor for spleen volume assessment due to induction of spleen flare after discontinuation: Patients who were not on ruxolitinib had better responses than those receiving ruxolitinib at baseline assessment, exemplified by a mean SVR of 21% in 14 patients off ruxolitinib compared with a 3% increase in spleen volume in 11 patients on ruxolitinib at baseline
• In terms of percentage change in CD34+ from baseline, there were rapid and dose-dependent reductions at all dose levels at Weeks 12 and 24, with greatest reductions observed with 240 mg
• Best TSS response with 120 mg/21-day, 240 mg/21-day, and 240 mg/28-day cohorts was 23%, 29%, and 30%, respectively

Safety¹

The most common treatment-emergent adverse event (TEAE) was diarrhea with 81% (all grades) and other gastrointestinal adverse events of all grades such as nausea, vomiting, and abdominal pain seen in 45%, 21%, and 20% of patients, respectively.

Reasons for discontinuation were withdrawal by patients (18%), adverse events (16%), investigator decision (11%), progressive disease (4%), death (4%), and other (4%).

The frequency of Grade 3–4 TEAEs was 78% in the overall population. The most common TEAEs are summarized in Table 2, below.

Table 2. The most common Grade ≥ 3 TEAEs (≥ 10% of patients) across the three cohorts¹

Grade 5 TEAEs that were considered related to the KRT-232 treatment included hemorrhagic stroke (240 mg, 21-day) and endocarditis (240 mg, 28-day).

Conclusion

This study represents the first clinical proof-of-concept approach to evaluate the role of MDM2 inhibitor in treating R/R MF. The MDM2 inhibitor, KRT-232, has been associated with a promising efficacy and safety profile in patients with R/R MF. Responses were dose-dependent; however, the reduction in spleen volume should be interpreted carefully due to confounding spleen flare related to late ruxolitinib discontinuation, as no washout period was required. A dosing schedule of 240 mg in a 28-day cycle will be further investigated in a randomized phase III study which will include patients with R/R MF who have failed JAK inhibitor treatment.

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