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Official Title

A Phase Ib Study of the Pharmacokinetics, Safety and Efficacy of Orally Administered HQP1351 in Subjects With Refractory Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL)

Phase
Phase 1
Sponsor
Ascentage Pharma Group Inc.
Enrollment
242
Timeline
Jan 2020 → Mar 2030
About This Study

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 Criteria

Inclusion Criteria

  • 1For HQP1351 monotherapy, patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL, with or without T315I mutation
  • 2For 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
  • 3For 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.
  • 4The 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:
  • 5Three months after the initiation of therapy: non-complete hematologic response (CHR) and/or Ph+ \>95%
  • 6Six months after the initiation of therapy: BCR-ABL1\>10% and/or Ph+ \>35%
  • 7Twelve months after the initiation of therapy: BCR-ABL1\>1% and/or Ph+ \>0%
  • 8Then, 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+)
  • 9The definition of resistance to second-line TKI treatment
  • 10a) For CML CP patients: the patients must meet at least one criterion as follows:
  • 11i.) Three months after the initiation of therapy: No CHR or Ph+ \>95% or new mutations
  • 12ii.) Six months after the initiation of therapy: BCR-ABL1\>10% and/or Ph+ \>65% and/or new mutations
  • 13iii.) Twelve months after the initiation of therapy: BCR-ABL1\>1% and/or Ph+ \>35% and/or new mutations
  • 14iv.) 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+)
  • 15b) For CML AP patients: the patients must meet at least one criterion as follows:
  • 16i.) Three months after the initiation of therapy: failure to achieve a major hematologic response (MaHR)
  • 17ii.) 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
  • 18iii.) At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR
  • 19c) For CML BP and Ph+ ALL patients: the patients must meet at least one criterion as follows:
  • 20i) One month after the initiation of therapy: failure to achieve a MaHR
  • 21ii) 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
  • 22iii) At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR
  • 23Intolerance to TKIs is defined as:
  • 24Non-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
  • 25Hematological 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
  • 26Patients providing written informed consent before initiation of any study-related activities
  • 27Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  • 28Minimum life expectancy of 3 months or more
  • 29Patients with adequate organ function as defined below:
  • 30Creatinine \< 2 × upper limit of normal (ULN); or, creatinine \> 2 × ULN, with 24h glomerular filtration rate (GFR) ≥ 30 mL/min (Cockcroft-Gault)
  • 31Serum albumin ≥ 3.0 g/dL
  • 32Total bilirubin \< 1.5 × ULN
  • 33Aspartate 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)
  • 34Serum amylase and lipase ≤ 1.5 × ULN
  • 35Prothrombin time (PT) ≤ 1.5 × ULN
  • 36Heart function: Left ventricular ejection fraction (LVEF) \> 50%
  • 37Normal QT interval corrected Fridericia (QTcF) interval on screening electrocardiogram (ECG) evaluation: male ≤450ms, female ≤470ms
  • 38For 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
  • 39Ability to comply with study procedures, in the Investigator's opinion

Exclusion Criteria

  • 1Received 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
  • 2Received other therapies as follows:
  • 3For 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
  • 4For BP patients, received chemotherapy within 7 days prior to the first dose of HQP1351
  • 5For 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
  • 6Patients who are currently receiving treatment with a medication that has the potential to interact with HQP1351
  • 7Patients who had been treated with HQP1351
  • 8Patients requiring immunosuppressive therapy other than short time of steroid
  • 9Impairment of gastrointestinal (GI) function or GI disease that may significantly alter absorption of study drugs
  • 10Patients 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.
  • 11Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
  • 12Any history of myocardial infarction (MI) within 6 months or unstable angina within 3 months
  • 13Any history of cerebrovascular accident within 1 year, or transient ischemic attack (TIA) within 3 months
  • 14Any history of peripheral vascular infarction, including visceral infarction within 6 months
  • 15Congestive 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
  • 16History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia
  • 17Venous 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.
  • 18Patients with revascularization procedures including cardiac bypass within the 6 months and stenting within the past 3 months should be excluded.
  • 19Have 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
  • 20CML CP patients with CCyR
  • 21Patients who have a significant bleeding disorder unrelated to CML or Ph+ ALL
  • 22Patients 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
  • 23Cytologically confirmed central nervous system (CNS) involvement (if asymptomatic, spinal fluid examination is not necessary prior to first treatment)
  • 24Patients 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.
  • 25Have 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.
  • 26Patients with COVID-19 who now present with positive swab
  • 27Patients who have poorly controlled diabetes, defined as HbA1C values of \> 7.5%. Patients with pre-existing, well-controlled diabetes are not excluded.
  • 28Known allergy to any components in the study drug
  • 29Pregnant or lactating
  • 30Patients 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

Locations

9 sites participating in this study

Winship Cancer Institute, Emory University

Atlanta, Georgia 30322

Recruiting

Anthony Hunter, MD

University of Alabama at Birmingham

Birmingham, Alabama 35294

Recruiting

Omer Jamy, MD

City of Hope

Duarte, California 91010

Recruiting

Paul Koller, MD

Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →