An Updated Safety and Efficacy Results of Phase 1 Study of HQP1351, a Novel 3^rd Generation of BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI Resistant Chronic Myeloid Leukemia

Background: HQP1351, a novel, orally active potent 3^rd generation TKI, was designed for treatment of patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation. This is an updated report of the safety and efficacy of HQP1351.

Methods: It is an open-label, dose escalation and expansion phase 1 trial of HQP1351 which was designed to determine maximum tolerated dose (MTD) and to identify dose-limiting toxicities (DLTs) in patients with CML in the chronic phase (CP) or accelerated phase (AP) resistant or intolerant to ≥ 2 prior TKIs or those with T315I mutation after ≥1 prior TKI. HQP1351 was orally administered once every other day (QOD) in 28-day cycles at 11 dose cohorts ranging from 1mg to 60 mg. The eligible patients received continuous treatments until disease progression to AP or BP, developing intolerant toxicity, consent withdrawal, or death. Blood samples were collected at certain time points on Day 1-2 and Day 27-28 during cycle 1 for PK analyses.

Results: From 26 October, 2016 to 27 May, 2019, 101 patients including 87 CP patients and 14 AP patient were enrolled in this study. Seventy-one (70.3%) patients were male. Median duration of follow-up was 12.8 (range, 1.2-31.5) months. Median age was 40 (range, 20-64) years. Median interval from CML diagnosis to starting HQP1351 treatment was 5.8 (range, 0.3-15.2) years. Eighty-three (83.8%) patients received ≥2 prior lines of TKI-therapy. Sixty-two (61.4%) patients harbored T315I mutation. Seventeen patients who initially assigned to the dose escalation cohorts ranging from 1mg to 20 mg moved to 30 mg or higher dose cohorts via intra-patient dose escalation. Fifty-six patients enrolled in the dose expansion part of the trial, including 30mg,40mg and 50mg dose cohorts. Two out of 3 patients at 60mg dose cohort experienced DLT and 50mg QOD was considered as the MTD.

During the follow-up period, HQP1351 was well-tolerated in each dose cohort with an exception of 60 mg cohort. All patients experienced ≥1 treatment related adverse events (TRAEs), most of the non-hematologic TRAEs were reported as grade 1 or grade 2. The most common hematologic TRAE of grade 3/4 was thrombocytopenia (49.5%). The incidences of TRAEs tended to be dose-dependent. No death and grade 5 AEs occurred. The incidence of common TRAEs (≥ 10% any grade) are summarized in Table1.

HQP1351 showed potent anti-leukemic activities in CML patients. In the 68 evaluable patients with non-CHR at baseline, 63 (92.6%) achieved CHR including 52 out of 55 (94.5%) CP patients and 11 out of 13 (84.6%) AP patients, respectively. In the 95 evaluable patients with non-CCyR at baseline, 56 out of 81 (69.1%) CP patients achieved MCyR including 49 (60.5%) CCyR; and 6 out of 14 (42.9%) AP patients, achieved MCyR including 5 (35.7%) CCyR, respectively. In the 100 evaluable patients, 32 out of 86 (37.2%) CP patients and 5 out of 14 (35.7%) AP patients achieved MMR, respectively. HQP1351 showed highly efficacious in the patients with T315I mutation (Figure A, B). The probability and the depth of response increased with prolonged treatment period (Figure C). As the cut-off date of May 27 2019, 9 patients (5 CP and 4 AP) withdrawn from the study, including progression to AP or BP (n=5), intolerant AEs (n=2), consent withdrawal (n=1), and newly diagnosis of breast cancer (n=1). The progression free survival (PFS) rate at 18-month was 94% in the CP patients and 61% in the AP patients (Figure D).

PK analyses indicated an approximately dose proportional increase in exposure (AUC and C_max) following oral administration of HQP1351 at doses from 1mg to 60 mg. The peak concentration of HQP1351 was reached at 4-8h. The elimination appeared to be linear with a mean terminal T_1/2 of 17.5 to 42.5 h. Slight to moderate accumulation was observed on Day 27 following multiple dosing. Reduction of CRkL phosphorylation in PBMCs, a biomarker of BCR-ABL inhibition, has shown to be dose and time dependent in 53 evaluable patients treated with HQP1351.

Conclusions: HQP1351 was well tolerated and exhibited significant and durable antitumor activity in the patients with TKI-resistant CML, including those with T315I mutation. Two pivotal studies of HQP1351 in CML-CP and CML-AP patients with T315I mutation are ongoing in China.

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