RECRUITING

Study of HQP1351 in Subjects With Refractory CML and Ph+ ALL

Conditions

Leukemia, Myeloid, Chronic Myeloid Leukemia Chronic Myeloid Leukemia Philadelphia Positive Acute Lymphoblastic Leukemia B Cell Precursor Type Acute Leukemia T315I mutation Chronic Phase Accelerated Phase Blast Phase Lymphoid blast phase

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

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)

Quick Facts

Study Start:2020-01-09

Study Completion:2024-01-31

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT04260022

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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 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	* 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

Inclusion Criteria

Exclusion 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
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

* 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

Contacts and Locations

Study Contact

Bill Garrett

CONTACT

301-520-3962

Bill.Garrett@ascentage.com

Principal Investigator

Yifan Zhai, MD, PhD

STUDY_CHAIR

Ascentage Pharma Group Inc.

Study Locations (Sites)

University of Alabama at Birmingham

Birmingham, Alabama, 35294

United States

Highlands Oncology

Rogers, Arkansas, 72758

United States

City of Hope

Duarte, California, 91010

United States

Winship Cancer Institute, Emory University

Atlanta, Georgia, 30322

United States

University of Maryland

Baltimore, Maryland, 21201

United States

Cleveland Clinic

Cleveland, Ohio, 44195

United States

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030

United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109

United States

Collaborators and Investigators

Sponsor: Ascentage Pharma Group Inc.

Yifan Zhai, MD, PhD, STUDY_CHAIR, Ascentage Pharma Group Inc.

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2020-01-09

Study Completion Date2024-01-31

Study Record Updates

Study Start Date2020-01-09

Study Completion Date2024-01-31

Terms related to this study

Keywords Provided by Researchers

T315I mutation
Chronic Phase
Accelerated Phase
Blast Phase
Lymphoid blast phase

Additional Relevant MeSH Terms

Leukemia, Myeloid, Chronic
Myeloid Leukemia
Chronic Myeloid Leukemia
Philadelphia Positive Acute Lymphoblastic Leukemia
B Cell Precursor Type Acute Leukemia