Overview

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.

Eligibility

Inclusion Criteria:

• 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
• 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
• 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.
  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, 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

     1. Three months after the initiation of therapy: non-complete hematologic response (CHR) and/or Ph+ >95%
     2. Six months after the initiation of therapy: BCR-ABL1>10% and/or Ph+ >35%
     3. Twelve months after the initiation of therapy: BCR-ABL1>1% and/or Ph+ >0%
     4. 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+)

  2. The definition of resistance to second-line TKI treatment
     1. 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
               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 AP/BP or Ph+ ALL patients
                    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/BP or Ph+ ALL patients
          -  Patients providing written informed consent before initiation of any study-related
             activities
          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤2
          -  Minimum life expectancy of 3 months or more
          -  Patients with adequate organ function as defined below:
               1. Creatinine < 2 × upper limit of normal (ULN); or, creatinine > 2 × ULN, with 24h
                  glomerular filtration rate (GFR) ≥ 30 mL/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)])
                  < 3 × 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
          -  Heart function: Left ventricular ejection fraction (LVEF) > 50%
          -  Normal QT interval corrected Fridericia (QTcF) interval on screening electrocardiogram
             (ECG) evaluation: male ≤450ms, female ≤470ms
          -  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
          -  Ability to comply with study procedures, in the Investigator's opinion
        Exclusion Criteria:
          -  Received TKI therapy within 5 half-lives or 7 days prior to first dose of HQP1351,
             whichever is shorter, or any adverse events (AEs) (except alopecia and pigmentation)
             not recovered to CTCAE v5.0 grade 0-1 due to any other treatments
          -  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. For BP patients, received chemotherapy within 7 days prior to the first dose of
                  HQP1351
               3. For Ph+ ALL patients, received corticosteroids within 24 hours before the first
                  dose of HQP1351, or received chemotherapy within 7 days prior to the first dose
                  of HQP1351
               4. Patients who are currently receiving treatment with a medication that has the
                  potential to interact with HQP1351
               5. Patients who had been treated with HQP1351
               6. Patients requiring immunosuppressive therapy other than short time of steroid
          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter absorption of study drugs
          -  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. Patients with well controlled HBP can be considered to be
             included. ("well controlled HBP" is defined as: HBP can be ≤ 140/90mmHg with
             antihypertensive treatment). Those requiring 3 or more antihypertensive medications
             should be discussed with the medical monitor.
          -  Have clinically significant, uncontrolled, or active cardiovascular disease,
             specifically including, but not restricted to:
               1. Any history of myocardial infarction (MI) within 6 months or unstable angina
                  within 3 months
               2. Any history of cerebrovascular accident within 1 year, or transient ischemic
                  attack (TIA) within 3 months
               3. Any history of peripheral vascular infarction, including visceral infarction
                  within 6 months
               4. Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or
                  IV) within 6 months prior to enrollment, or left ventricular ejection fraction
                  (LVEF) less than lower limit of normal, per local institutional standards, within
                  6 months prior to enrollment
               5. History of clinically significant (as determined by the treating physician)
                  atrial arrhythmia or any history of ventricular arrhythmia
               6. Venous thromboembolism, including deep venous thrombosis or pulmonary embolism,
                  within 3 months prior to enrollment. Patients who have experienced a venous
                  thromboembolic event should only be eligible if the condition is well controlled
                  with optimal intervention (as determined by the treating physician). Continued
                  prophylactic anticoagulation is acceptable.
               7. Patients with revascularization procedures including cardiac bypass within the 6
                  months and stenting within the past 3 months should be excluded.
          -  Have history of autologous or allogeneic stem cell transplant, or with active
             graft-versus-host disease (GVHD), or active immune suppression in recent 6 months
             prior to informed consent date or active immune suppression in recent 6 months prior
             to informed consent date
          -  CML CP patients with CCyR
          -  Patients who have a significant bleeding disorder unrelated to CML or Ph+ ALL
          -  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
          -  Cytologically confirmed central nervous system (CNS) involvement (if asymptomatic,
             spinal fluid examination is not necessary prior to first treatment)
          -  Patients with another primary malignancy within 1 year of study entry. Patients with
             nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have
             undergone complete resection and are considered disease-free at the time of study
             entry.
          -  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.
          -  Patients with COVID-19 who now present with positive swab
          -  Patients who have poorly controlled diabetes, defined as HbA1C values of > 7.5%.
             Patients with pre-existing, well-controlled diabetes are not excluded.
          -  Known allergy to any components in the study drug
          -  Pregnant or lactating
          -  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