Summary

A multi-center, open-label, randomized, phase Ib study to evaluate the pharmacokinetics
(PK) of HQP1351 and to determine the recommended phase 2 dose (RP2D) of HQP1351 in
subjects with CML chronic phase (CP), accelerated phase (AP), or blast phase (BP) or with
Ph+ ALL, who have experienced resistance or intolerance to at least two tyrosine kinase
inhibitors (TKIs) or in subjects with Ph+ B-cell precursor (BCP) ALL or lymphoid blast
phase CML (CML LBP), who have experienced resistance or intolerance to at least one
second or later generation TKI.

Objectives

Approximately 40 patients will be randomized at 3:3:2 ratio into one of three HQP1351
monotherapy dose cohorts (Cohort A, B, and C): 30 mg every other day (QOD), 40 mg QOD,
and 50 mg QOD, with 15, 15, and 10 patients in Cohort A, B, and C. The first cycle of 28
days is considered as the dose-limiting toxicity (DLT) observation period. If the
incidence of DLTs exceeds 20% (2 patients) in 50 mg dose cohort during the first cycle of
therapy, this dose cohort will be stopped. The randomization will be stratified to 4
groups: T315I mutated CML-CP and CML-AP, T315I un-mutated CML-CP, T315I unmutated CML-AP,
and CML-BP and Ph+ ALL to ensure that the subgroups are represented across all dose
cohorts. Blood samples will be collected from each subject at specified time points to
evaluate the PK of HQP1351. RP2D of HQP1351 will be determined based on the comprehensive
analyses of the PK, safety, and efficacy data of the US patients treated with HQP1351,
when compared with that in the Chinese patients.

Eligible patients will have disease resistance to or intolerance to at least two TKIs,
for patients with T315I mutation, number of pretreated TKIs is not restricted. Patients
will be administered HQP1351 orally QOD during a period of 28 days (1 cycle).

Cohort D (HQP1351 + blinatumomab) will enroll patients with relapsed/refractory Ph+ BCP
ALL or CML-BP using a dose escalation and expansion design. Patients will be administered
HQP1351 orally QOD at an assigned dose with blinatumomab at repeated 42-day cycles. The
first cycle of 42 days is considered as the DLT observation period. The initial dose of
HQP1351 will be 30 mg QOD.

Eligibility

1. For HQP1351 monotherapy, patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL, with or without T315I mutation
2. For Cohort D, patients with Ph+ BCP ALL or CML LBP must be resistant or intolerant to at least one second or later generation TKI, such as dasatinib, nilotinib, bosutinib and ponatinib, despite optimal supportive care
3. For HQP1351 monotherapy only: Be previously treated with and developed resistance or intolerance to at least two TKIs including ponatinib, imatinib, dasatinib, nilotinib, bosutinib, and asciminib. For patients with a T315I mutation, number of pretreated TKIs is not restricted.
4. The definition of resistance to first-line TKI treatment refers to European Leukemia Net (ELN) recommendations. The definitions are the same for patients in CP, AP, BP, and Ph+ ALL, and apply also to second-line treatment, when first-line treatment was changed for intolerance. The patients must meet at least one criterion:
5. Three months after the initiation of therapy: non-complete hematologic response (CHR) and/or Ph+ >95%
6. Six months after the initiation of therapy: BCR-ABL1>10% and/or Ph+ >35%
7. Twelve months after the initiation of therapy: BCR-ABL1>1% and/or Ph+ >0%
8. Then, and at any time after the initiation of therapy: Loss of CHR, or loss of complete cytogenetic response (CCyR), or confirmed loss of major molecular response (MMR) (In 2 consecutive tests, of which one with a BCR-ABL1 transcripts level =1%), mutations, clonal chromosome abnormalities in Ph+ cells (CCA/Ph+)
9. The definition of resistance to second-line TKI treatment a) For CML CP patients: the patients must meet at least one criterion as follows: i.) Three months after the initiation of therapy: No CHR or Ph+ >95% or new mutations ii.) Six months after the initiation of therapy: BCR-ABL1>10% and/or Ph+ >65% and/or new mutations iii.) Twelve months after the initiation of therapy: BCR-ABL1>1% and/or Ph+ >35% and/or new mutations iv.) Then, and at any time after the initiation of therapy: Loss of CHR or loss of CCyR, new mutations, confirmed loss of MMR (In 2 consecutive tests, of which one with a BCR-ABL1 transcripts level =1%), clonal chromosome abnormalities in Ph+ cells (CCA/Ph+) b) For CML AP patients: the patients must meet at least one criterion as follows: i.) Three months after the initiation of therapy: failure to achieve a major hematologic response (MaHR) ii.) At any time after the initiation of therapy, the loss of a MaHR, confirmed in at least 2 consecutive analyses separated by at least 4 weeks iii.) At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR c) For CML BP and Ph+ ALL patients: the patients must meet at least one criterion as follows: i) One month after the initiation of therapy: failure to achieve a MaHR ii) At any time after the initiation of therapy, the loss of a MaHR, confirmed in at least 2 consecutive analyses separated by at least 1 week iii) At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR
10. Intolerance to TKIs is defined as:
11. Non-hematological AEs: patients with grade 3 or 4 toxicity during TKIs treatment, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments in the absence of a CCyR for CP patients or MaHR for AP/BP or Ph+ ALL patients
12. Hematological AEs: patients with grade 3 or 4 toxicity during TKIs treatment, that is recurrent after unresponsive after optimal management, including dose adjustments in the absence of a CCyR for CP patients or MaHR for AP/BP or Ph+ ALL patients
13. Patients providing written informed consent before initiation of any study-related activities
14. Eastern Cooperative Oncology Group (ECOG) performance status =2
15. Minimum life expectancy of 3 months or more
16. Patients with adequate organ function as defined below:
17. Creatinine < 2 × upper limit of normal (ULN); or, creatinine > 2 × ULN, with 24h glomerular filtration rate (GFR) = 30 mL/min (Cockcroft-Gault)
18. Serum albumin = 3.0 g/dL
19. Total bilirubin < 1.5 × ULN
20. Aspartate aminotransferase (AST [Serum glutamic oxaloacetic transaminase (SGOT)]) and alanine aminotransferase (ALT [serum glutamate-pyruvate transaminase (SGPT)]) < 3 × ULN for institution (<5×ULN if liver involvement with leukemia)
21. Serum amylase and lipase = 1.5 × ULN
22. Prothrombin time (PT) = 1.5 × ULN
23. Heart function: Left ventricular ejection fraction (LVEF) > 50%
24. Normal QT interval corrected Fridericia (QTcF) interval on screening electrocardiogram (ECG) evaluation: male =450ms, female =470ms
25. For females of childbearing potential, a negative pregnancy test must be established before enrollment. And the eligible female and male patients with childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study
26. Ability to comply with study procedures, in the Investigator's opinion

Treatment Sites in Georgia