A multi-center, open-label, randomized, phase Ib study to evaluate the PK of HQP1351 and to
determine the RP2D of HQP1351 in subjects with CML CP and AP,who have experienced resistance
or intolerance to at least two TKIs. .
This is a multi-center, open-label, randomized, phase Ib study to evaluate the PK of HQP1351
and to determine the RP2D of HQP1351 in subjects with CML CP and AP, who have experienced
resistance or intolerance to at least two TKIs. The preliminary efficacy and safety of
HQP1351 in these patients will be evaluated as well.
A total of 30 patients will be randomized at 1:1:1 ratio into one of the three dose cohorts:
30 mg every other day (QOD), 40 mg QOD and 50 mg QOD, with 10 patients per dose cohort. The
first cycle of 28 days is considered as the 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 3 groups: T315I mutated
CML-CP and CML-AP, T315I un-mutated CML-CP, and T315I unmutated CML-AP 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 kinds of TKIs.
Patients will be administered HQP1351 orally every other day (QOD) during a period of 28 days
1. Age ≥18 years old. 2. Patients must have CML in CP or AP of any phenotype, with or
without T315I mutation. 3. Be previously treated with and developed resistance or
intolerance to at least two TKIs (such as imatinib, dasatinib, nilotinib, bosutinib or
1. 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 and AP, and
apply also to second-line treatment, when first-line treatment was changed for
intolerance. The patients must meet at least one criterion. a) Three months after the
initiation of therapy: Non-CHR and/or Ph+ >95%. b) Six months after the initiation of
therapy: BCR-ABL1＞10% and/or Ph+ >35%. c) Twelve months after the initiation of
therapy: BCR-ABL1＞1% and/or Ph+ >0%. d) Then, and at any time after the initiation of
therapy：Loss of CHR, or loss of CCyR, or confirmed loss of MMR (In 2 consecutive
tests, of which one with a BCR-ABL1 transcripts level≥1%), mutations, clonal
chromosome abnormalities in Ph+ cells (CCA/Ph+).
2. 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＞10% 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 MaHR. Ascentage
Pharma Group Inc. Protocol HQP1351CU101 47 / 88 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.
3. Intolerance to TKIs is defined as:
1. 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
2. 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 patients. 4.
Patients providing written informed consent before initiation of any
study-related activities. 5. Eastern Cooperative Oncology Group (ECOG)
performance status ≤2. 6. Minimum life expectancy of 3 months or more. 7.
Patients with adequate organ function as defined below:
1) Creatinine < 1.5 × upper limit of normal (ULN); or, creatinine > 1.5 × ULN, with 24h GFR
≥50Ml/min (Cockcroft-Gault). 2) Serum albumin ≥ 3.0 g/dL. 3) Total bilirubin < 1.5 ×ULN. 4)
Aspartate aminotransferase (AST [Serum glutamic oxaloacetic transaminase (SGOT)]) and
alanine aminotransferase (ALT [serum glutamate-pyruvate transaminase (SGPT)]) < 2.5 × ULN
for institution (＜5×ULN if liver involvement with leukemia). 5) Serum amylase and lipase ≤
1.5 × ULN. 6) Prothrombin time (PT) ≤ 1.5 × ULN. 8. Heart function: Left ventricular
ejection fraction (LVEF) > 50%. 9. Normal QTcF interval on screening electrocardiogram
(ECG) evaluation: male
- 450ms，female ≤470ms. 10. 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. 11. Ability to comply
with study procedures, in the Investigator's opinion
- Received TKI therapy within 7 days prior to first dose of HQP1351, or, any adverse
events (AEs) (except alopecia and pigmentation) not recovered to CTCAE v5.0 grade 0-1
due to any other treatments. 2. Received other therapies as follows:
1. For CP and AP patients, received hydroxyurea or anagrelide within 24 hours prior
to the first dose of HQP1351; or, interferon, immunotherapy or cytarabine within
14 days prior to the first dose of HQP1351; or, any other radiotherapy, cytotoxic
chemotherapy or investigational therapy within 28 days prior to receiving the
first dose of HQP1351.
2. Patients who are currently receiving treatment with a medication that has the
potential to interact with HQP1351.
3. Patients who had been treated with HQP1351.
4. Patients requiring immunosuppressive therapy other than short time of steroid. 3.
Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter absorption of study drugs. 4. Patients with cardiovascular diseases,
including uncontrolled high blood pressure (HBP) (that is blood pressure
>140/90mmHg.); or, receiving drugs that can cause prolonged QT interval. The
patients with well controlled HBP can be considered to be included. (the "well
controlled HBP" is defined as: HBP can be ≤ 140/90mmHg with antihypertensive
treatment; the range of fluctuation of blood pressure in recent 6 months has been
no more than 160/90mmHg). Those requiring 3 or more antihypertensive medications
should be discussed with the medical monitor. 5. Have experience of serious
cardiovascular AEs, such as myocardial infarction, unstable angina, severe
arrhythmias, congestive heart failure during previous TKIs treatment. 6. Have
history of autologous or allogeneic stem cell transplant, or with active GVHD, or
active immune suppression in recent 6 months prior to informed consent date. 7.
CML CP patients with CCyR; or, CML AP patients with MaHR. 8. Patients who have a
significant bleeding disorder unrelated to CML. 9. Patients who had a major
surgery within 4 weeks prior to study entry or have not recovered from side
effects of such surgery which the Investigator considers not appropriate for
enrollment. 10. Cytologically confirmed central nervous system (CNS) involvement
(if asymptomatic, spinal fluid examination is not necessary prior to first
treatment). 11. Patients with another primary malignancy within 1 years of study
entry. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
not excluded if they Ascentage Pharma Group Inc. Protocol HQP1351CU101 49 / 88
have undergone complete resection and are considered disease-free at the time of
study entry. 12. Have ongoing or active infection, including known history of
immunodeficiency virus (HIV) or HIV antibody positive, hepatitis B virus (HBV) or
HBsAg positive, hepatitis C virus (HCV). Patients who have positive HCV antibody
must have an undetectable HCV viral load. 13. Known allergy to any components in
the study drug. 14. Pregnant or lactating. 15. Patients who have any conditions
or illness that, according to the opinions of the investigator or the medical
monitor, would comprise patient safety or interfere with the evaluation of safety
and efficacy to the study drug