Background: Outcomes for relapsed or refractory (R/R) acute myeloid leukemia (AML) remain poor despite advances in the treatment of AML. MEC, consisting of mitoxantrone, etoposide (ETOP), and cytarabine, is an established regimen for the treatment of R/R AML. Peposertib is a potent, selective, and oral DNA-PK inhibitor that disrupts DNA-PK mediated non-homologous end joining and repair of double-strand DNA breaks induced by anthracyclines (AC) and ETOP. Peposertib synergizes with AC and ETOP in preclinical studies. Peposertib inhibits CYP3A4, which is predicted to increase ETOP levels by up to 2-fold depending on the peposertib dose and could lead to increased toxicity. Thus, we tested the safety, pharmacokinetics (PK), and antileukemia activity of peposertib combined with MEC in patients with R/R AML.

Methods: This is a multicenter Phase I trial of peposertib in combination with MEC in patients with R/R AML (NCT03983824). A modified 3+3 design with a PK-based dose-escalation schema was used to determine the recommended phase 2 dose (RP2D), followed by a dose expansion part at the RP2D. Key eligibility criteria included age ≥18 years, AML diagnosis by WHO criteria, relapsed and/or refractory disease, and eligibility for AC. Patients received one cycle of treatment with peposertib plus MEC. There were up to 6 dose levels planned, 3 dose levels with MEC with a reduced ETOP dose of 50mg/m2 D1-5, and peposertib dosed at 100mg, 200mg, or 400mg PO BID D2-21 (Dose Levels A1, A2, and A3) and 3 dose levels with ETOP at the standard dose of 100mg/m2, with peposertib at either 100mg, 200mg, or 400mg PO BID D2-21 (Levels A4, A5, and A6). Peposertib was given D2-21 to allow for MEC only PK analysis. Bone marrow biopsies, PK, and pharmacodynamic (PD) testing were obtained pre- and post-treatment. The primary objective was to determine safety and tolerability. Adverse events (AE) were monitored throughout treatment, and dose-limited toxicities (DLT) assessed up to day 28. Secondary and exploratory objectives were to evaluate PK and preliminary efficacy and PD, respectively. Responses were per European LeukemiaNet (ELN) 2017 criteria.

Results: Enrollment was completed, with 37 patients enrolled (Levels A1 n=3, A2 n=13, A3 n=3, A4 n=12, and A5 n= 6). Median age was 58 years (range 23-74). Of the patients enrolled, 62% (n=22) were male, 5% (n=2) were Asian, 5% (n=2) were Black, and 49% (n=18) identified as Hispanic or Latino. All patients had an ECOG PS of 0-1. Per ELN 2022 criteria, risk was adverse in 62% (n=23), while 65% (n=24) and 35% (n=13) had relapsed and refractory AML, respectively. Median prior lines of therapy received was 2 (range 1-6), including prior venetoclax in 78% (n=29) of patients.

During dose escalation, there were no DLT on A1 (0/3) or A2 (0/6), 2 DLT on A3 (2/3, both grade 3 mucositis), 1 DLT on A4 (1/6, grade 3 rash maculo-papular), and 2 DLT on A5 (2/3, 1 grade 3 mucositis and 1 grade 5 sepsis). Dose level A6 was not explored due to DLT in A3 and A5. As a result, both A2 (lower ETOP/higher peposertib) and A4 (standard ETOP/lower peposertib) were expanded, with a total of 13 patients treated on A2 and 12 patients treated on A4. The majority of patients on both dose levels were able to receive the full treatment without interruption. On cohorts A2 and A4, the 30-day mortality was 1/12 and 0/12, and 60-day mortality was 3/12 and 1/12, respectively, with 1 unknown on A2. To date, all patients are off treatment.

Among the 37 patients started on protocol therapy, 27% (n=10) had an antileukemia response, including 3 complete remission (CR), 6 CR with incomplete count recovery (CRi), and 1 partial remission (PR). The CR/CRi rate was 24.3% (n=9). On level A2, 5/13 patients responded (2 CR, 2 CRi, and 1 PR), and on dose level A4, 3/12 responded (1 CR and 2 CRi). PK analyses from dose levels A1, A2, A3, A4, and A5 showed no increase in ETOP area under the curve with the addition of peposertib.

Conclusions: Overall, combining peposertib with MEC was feasible and did not significantly affect ETOP PK. Despite the high risk and heavily pretreated study population, including 78% with prior venetoclax, activity was seen on multiple dose levels, including A2 and A4, which were both expanded and remain RP2D candidates after expansion. Additional PK and PD analyses, follow-up, and evaluation of duration of remission, event-free survival, and overall survival, will aid in selecting the final RP2D and informing future studies.

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2025
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