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Study of HQP1351 in Subjects With Refractory Chronic Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04260022
Recruitment Status : Recruiting
First Posted : February 7, 2020
Last Update Posted : August 12, 2020
Sponsor:
Information provided by (Responsible Party):
Ascentage Pharma Group Inc.

Brief 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 CP and AP, who have experienced resistance or intolerance to at least two tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib or ponatinib.

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Chronic Myeloid Leukemia Chronic Myeloid Leukemia Drug: Ascentage Pharma HQP1351 bioavailable inhibitor Phase 1

Detailed Description:

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 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 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 cycle).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Study of the Pharmacokinetics, Safety and Efficacy of Orally Administered HQP1351 in Subjects With Refractory Chronic Myeloid Leukemia (CML)
Actual Study Start Date : December 1, 2019
Estimated Primary Completion Date : December 30, 2021
Estimated Study Completion Date : December 30, 2023


Arm Intervention/treatment
Experimental: HQP1351 30mg Drug: Ascentage Pharma HQP1351 bioavailable inhibitor
HQP1351 taken by mouth every other day

Experimental: HQP1351 40mg Drug: Ascentage Pharma HQP1351 bioavailable inhibitor
HQP1351 taken by mouth every other day

Experimental: HQP1351 50mg Drug: Ascentage Pharma HQP1351 bioavailable inhibitor
HQP1351 taken by mouth every other day




Primary Outcome Measures :
  1. Maximum Plasma Concentration (Cmax) of HQP1351 [ Time Frame: 27 days ]
    To evaluate the Maximum Plasma Concentration (Cmax) of HQP1351

  2. Area Under the Curve (AUC) of HQP1351 [ Time Frame: 27 days ]
    To evaluate the Area Under the Curve (AUC) of HQP1351



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have CML in chronic phase (CP) or accelerated phase (AP) of any phenotype, with or without T315I mutation
  • Be previously treated with and developed resistance or intolerance to at least two TKIs (such as imatinib, dasatinib, nilotinib, bosutinib or ponatinib)

    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.

      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>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+)
      2. 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
    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 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 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 < 1.5 × upper limit of normal (ULN); or, creatinine > 1.5 × ULN, with 24h glomerular filtration rate (GFR) ≥ 50 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)]) < 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
  • 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 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
  • 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
  • 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. 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.
  • Have experience of serious cardiovascular AEs, such as myocardial infarction, unstable angina, severe arrhythmias, congestive heart failure during previous TKIs treatment
  • 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
  • CML CP patients with CCyR; or CML AP patients with MaHR
  • Patients who have a significant bleeding disorder unrelated to CML
  • 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 years 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.
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04260022


Contacts
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Contact: Kathryn Shantz 301-802-3414 kate.shantz@ascentage.com
Contact: Jennifer Coe 301-509-4381 jennifer.coe@ascentage.com

Locations
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United States, Arkansas
Highlands Oncology Recruiting
Rogers, Arkansas, United States, 72758
Contact: Thad Beck, MD    479-936-9900      
Principal Investigator: Thad Beck, MD         
United States, Georgia
Winship Cancer Institute, Emory University Recruiting
Atlanta, Georgia, United States, 30322
Principal Investigator: Rebecca Klisovic, MD         
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Elias Jabbour, MD    713-792-7305      
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Principal Investigator: Vivian Oehler, MD         
Sponsors and Collaborators
Ascentage Pharma Group Inc.
Investigators
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Study Chair: Yifan Zhai, MD, PhD Ascentage Pharma Group Inc.
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Responsible Party: Ascentage Pharma Group Inc.
ClinicalTrials.gov Identifier: NCT04260022    
Other Study ID Numbers: HQP1351CU101
First Posted: February 7, 2020    Key Record Dates
Last Update Posted: August 12, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ascentage Pharma Group Inc.:
T315I mutation
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases