Safety and Efficacy of HQP1351, a 3rd Generation Oral BCR-ABL Inhibitor in Patients with Tyrosine Kinase Inhibitor—Resistant Chronic Myelogenous Leukemia: Preliminary Results of Phase I Study
Authors: Jiang Qian , Huang Xiao Jun , Chen Zi , Men Lichuang , Liu Wei , Sun Xuemei , JI Jiao , Wang Hengbang , Hou Yue , Hu Po , Zou Lei , Yan Hua , Huang Yingjie , Yang Dajun , Zhai Yifan 
Published: October 2019

Abstract
Background: HQP1351, a novel, potent 3rd generation TKI, was designed to treat patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation.
Aims: A single-agent, open-label dose escalation and dose expansion Phase I study to assess the safety, preliminary efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) properties of orally administered HQP1351 in the TKI-resistant patients with chronic phase (CP) or accelerated phase (AP) CML.
Methods: HQP1351 was administered once every other day (QOD) in 28-days cycles at 11 dose cohorts ranging from 1mg to 60 mg. The eligible patients received treatments until disease progression or intolerable toxicities. The primary efficacy endpoint in the CML AP and CP patients, was complete hematological response (CHR) and major cytogenetic response (MCyR) respectively, MCyR includes partial cytogenetic response (PCyR) and complete cytogenetic response (CCyR).Blood samples were collected at various time points on Day 1-2 and Day 27-28 during cycle 1 for PK analyses. BCR-ABL inhibition was evaluated using tyrosine phosphorylation of CRKL and STAT5 in peripheral blood mononuclear cell (PBMCs) collected from the patients before and 4, 8, 24 and 48 hours post HQP1351 treatments on Day 1, 15 and 27 during cycle 1.
Results:
From November 2016 to July 2018, 70 patients (CP n=58 and AP n=12) enrolled received ≥1 cycle of HQP1351-treatment, only 1 patient withdrew from the study due to disease progression. Median age was 39 (range: 23-59) years. Median interval from CML diagnosis to starting HQP1351-treatment was 6.1 (1.1-14.7) years. Sixty-one (87%) patients received ≥2 prior lines of TKI-therapy. Fifty-three (76%) patients had BCR-ABL mutations and 45 (64%) had T315I mutation at baseline.
With a median follow-up of 4.1 (1.0-21.2) cycles, HQP1351 was well-tolerated in all dose cohorts other than the 60mg cohort. In all patients, 67 (96%) patients experienced ≥1 treatment related adverse events (TRAEs) and 44 (63%) experienced TRAE(s) of grade 3-4 (Table 1). There was no patient withdrawal from the study because of TRAEs. Two out of 3 patients in the 60mg cohort experienced dose-limiting toxicity(DLT) and HQP1351 at 50mg QOD was considered as MTD.
The anti-leukemic activities of HQP1351 were observed in this study. Sixty-five (93%) patients including 58 (100%) CP and 7 (58%) AP patients achieved CHR at the dose of 2mg to 60mg within 3 cycles. In 47 evaluable patients receiving HQP1351-treatment ≥3 cycles, 24 (51%) achieved MCyR including 21 (54%) CP and 3 (38%) AP patients at the dose of 12mg to 50mg, and 14 (30%) patients achieved CCyR including 12 (31%) CP and 2 (25%) AP patients. Total 6 (15%) CP patients achieved MMR. More than 65% of the patients achieved MCyR or MMR at the end of cycle 3. HQP1351 was highly active in patients with or without T315I mutation at baseline (Table 2).
Following oral administration of HQP1351 at doses ranging from 1mg to 60 mg, the peak concentration was reached at 2-8 hrs. The elimination appeared to be linear with a mean terminal T1/2 of 15.3-36.5 hrs on Day 1, 18.8-42.5 hrs on Day 27, respectively. The ratios for AUC0-t and Cmax of HQP1351 on Day 27 versus Day 1 ranged from 1.03 to 2.12 and from 0.78 to 1.93, respectively. Thus, HQP1351 exhibited an approximately dose proportional increase in Cmax and AUC0-t following single or multiple oral administration dose ranging from 1 to 60 mg. PD study results demonstrated that reduction of CRKL phosphorylation was schedule and dose-dependent, ≥50% reduction was observed at doses ranging 12mg-60mg.
Conclusions: The preliminary results of the phase 1 study showed that HQP1351, a novel 3rd-generation TKI, is safe and highly active in treatment of the TKI-resistant patients with CP-CML and AP-CML,with or without T315I mutation.

Disclosures
Chen: HealthQuest Pharma Inc.: Employment. Men:HealthQuest Pharma Inc.: Employment. Liu:HealthQuest Pharma Inc.: Employment. Sun:HealthQuest Pharma Inc.: Employment. JI:HealthQuest Pharma Inc.: Employment. Wang:HealthQuest Pharma Inc.: Employment. Hu:HealthQuest Pharma Inc.: Employment. Zou:HealthQuest Pharma Inc.: Employment. Yan:HealthQuest Pharma Inc.: Employment. Huang:Ascentage Pharma Group Inc.: Employment; HealthQuest Pharma Inc.: Employment. Yang:Ascentage Pharma Group Inc.: Employment. Zhai:Ascentage Pharma Group Inc.: Employment.