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

Aug 7, 2020
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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 design1,2

  • A multicenter, global, randomized phase II study with two parts
  • Eligibility criteria: Age ≥ 18 years, TP53WT 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

C1D1, cycle 1 day 1; DIPSS, Dynamic International Prognostic Scoring System; ET, essential thrombocythemia; MF, myelofibrosis; MRI/CT, magnetic resonance imaging/computed tomography; PMF, primary myelofibrosis; PV, polycythemia vera; TSS, total symptom score

Characteristic

240 mg, 28-day

(n = 32)

240 mg, 21-day

(n = 20)

120 mg, 21-day

(n = 30)

MF subtype, n (%)

PMF

Post-PV MF

Post-ET MF

 

20 (63)

10 (31)

2 (6)

 

14 (70)

2 (10)

4 (20)

 

21 (70)

5 (17)

4 (13)

DIPSS, n (%)

Intermediate-1

Intermediate-2

High-risk

 

6 (19)

15 (47)

10 (31)

 

5 (25)

9 (45)

6 (30)

 

11 (37)

10 (33)

9 (30)

High molecular-risk mutations, n (%)

19 (59)

12 (60)

16 (53)

Ruxolitinib relapsed/refractory, n (%)

13/19 (41/59)

8/12 (40/60)

8/22 (27/73)

Platelets – median (range), × 103/µL

131 (46–949)

140 (68–373)

127 (52–571)

Transfusion dependent, n (%)

13 (41)

8 (40)

9 (30)

Hemoglobin – median (range), g/dL

9.6 (6.3–13.2)

8.9 (6.6–15.3)

10.0 (6.3–14.5)

Median spleen volume, cm3 (range)

2525 (1063–7128)

2474 (651–4320)

2472 (952–7753)

Baseline modified TSS, median (range)

15.0 (0–46)

12.0 (0.7–44)

15.1 (0.3–44.7)

Time from baseline scan to C1D1, days (range)

14 (2–43)

11 (2–31)

11 (4–38)

On ruxolitinib at baseline MRI/CT, n (%)

14 (44)

11 (55)

15 (50)

 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

TEAE, treatment-emergent adverse events

*Mainly due to subject withdrawal, adverse events, or investigator decision

TEAE, n (%)

240 mg, 28-day

(n = 32)

240 mg, 21-day

(n = 20)

120 mg, 21-day

(n = 30)

Any TEAE

27 (84)

14 (70)

23 (77)

Hematologic TEAEs

Thrombocytopenia

11 (34)

4 (20)

9 (30)

Anemia

13 (41)

4 (20)

7 (23)

Neutropenia

4 (13)

5 (25)

2 (7)

Leukopenia

1 (3)

3 (15)

3 (10)

Non-hematologic TEAEs

Diarrhea

7 (22)

3 (15)

2 (7)

Nausea

3 (9)

0 (0)

3 (10)

Abdominal pain

3 (9)

0 (0)

1 (3)

Asthenia

3 (9)

2 (10)

0 (0)

Dose interruption

3 (9)

5 (25)

7 (23)

Dose reduction

15 (47)

7 (35)

9 (30)

Treatment discontinuation*

17 (53)

14 (70)

17 (56)

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.

Expert opinion

Why should we target MDM2 with small molecule inhibitor KRT-232 in patients with MF?

  1. Al-Ali HK, Delgado RG, Lange A, et al. KRT‑232, a first‑in‑class, murine double minute 2 inhibitor (MDM2i), for myelofibrosis (MF) relapsed or refractory (R/R) to Janus‑associated Kinase inhibitor (JAKi) treatment (TX). Oral abstract #S215. 25th EHA Annual Congress; Jun 13, 2020; Virtual.
  2. Clinicaltrials.gov. KRT-232 in subjects with PMF, post-PV MF, or post-ET MF who have failed a JAK inhibitor. https://clinicaltrials.gov/ct2/show/NCT03662126. Updated Nov 26, 2019. Accessed Jul 29, 2020.

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