Clinical trial NCT03883087: A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Chronic Phase With T315I Mutation
Official title: A Phase II Multi-center, Open Label Study of HQP1351 in Chinese Patients of Chronic Myeloid Leukemia With T315I Mutation in Chronic Phase
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia, Chronic Phase
Keywords: Chronic Myeloid Leukemia,CML
T315I mutation
TKI
CML-CP
HQP1351
Olverembatinib Tablets
Lead sponsor: Ascentage Pharma Group Inc.
Sponsor class: INDUSTRY
First posted: 2019-03-20
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy of HQP1351 in patients with chronic myeloid leukemia in chronic phase (CML-CP) harboring T315I mutation. The efficacy of HQP1351 was determined by evaluating the subjects' major cytogenetic response (MCyR).

Detailed description: This is an open, single-arm, multi-center phase 2 clinical study to evaluate the efficacy and safety of oral administrated HQP1351(40mg, QOD) in CML-CP patients with T315I mutation in China. A total of 40 CML-CP patients will be included in this pivotal study. After screening, eligible subjects will receive oral HQP1351 40mg on a continues once every other day dosing regimen , until disease progression, drug intolerance, or meet other treatment conditions to discontinue the study. During the course of treatment, each subject will be assessed regularly for hematological, cytogenetic and molecular responses. At the same time, safety information also will be evaluated.

Eligibility criteria: Inclusion Criteria:

1. Male or non-pregnant, non-lactating female patients who are 18 years of age or older.
2. CML-CP patients with positive Ph chromosome or BCR-ABL fusion genes.
3. After any targeted BCR-ABL1 tyrosine kinase inhibitors (TKI) treatment, CML-CP patients with T315I mutation.
4. Ability to understand and willingness to sign a written informed consent form. The consent form must be signed by the patient prior to any study-specific procedures.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
6. Predicted life expectancy of ≥3 months.
7. Organ function as indicated by the following laboratory indicators must be met（Hematological indicators require that no blood transfusion or any blood products or cytokines be used within 14 days prior to testing）:

   * Hemoglobin ≥8.0g/dL.
   * White blood cell count ≥ 3.0×10\^9/L.
   * Platelet count ≥ 75×10\^9/L.
   * Serum creatinine ≤ 1.5×upper limit of normal (ULN) or 24 hours calculated creatinine clearance ≥ 50mL/min when serum creatinine \>1.5×ULN (with Cockcroft-Gault formula).
   * Serum albumin ≥ 3.0 g/dL.
   * Total bilirubin ≤ 1.5 x ULN.
   * Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN.
   * Amylase≤1.5×ULN. Lipase≤1.5×ULN.
   * PT、APTT、INR≤1.5×ULN.
8. Cardiac function index: ejection fraction (EF) \> 50%, pulmonary arterial systolic pressure (PASP) ≤50 mmHg.
9. Corrected QT interval (QTc) on electrocardiogram (ECG) evaluation: QTc≤450ms in males or ≤470ms in females.
10. Males and females of childbearing potential and their partners voluntarily take contraceptive measures that the researchers believe are effective within 120 days from the signing of the informed consent to the last use of the research drug, or confirm that sterilization has been performed (at least one month before screening).
11. Willingness and ability to comply with study procedures and follow-up examination.

Exclusion Criteria:

1. Received chemotherapy or radiotherapy within 28 days prior to the first administration, interferon or antitumor effect Chinese herbal medicine or Chinese patent medicine within 14 days prior to the first administration, or targeted BCR-ABL1 TKI within 7 days prior to the first administration, or hydroxyurea or anagrelide within 24 hours after the first administration, or adverse events (except alopecia) caused by previous treatment and have not recovered.
2. The patients who received any other investigating drugs within 14 days prior to first administration.
3. Patients who have progressed to accelerated phase (AP) or blast phase (BP) in the past.
4. Patients who are currently receiving treatment with a medication that has the potential to interact with research drug
5. Have previously been treated with ponatinib or HQP1351 (or drugs of similar composition).
6. Absorption disorder syndrome or other diseases affecting oral drug absorption.
7. Have any history of heart or vascular disease, such as hypertension (systolic blood pressure (HBP)\> 140mmHg and/or diastolic blood pressure \> 90mmHg), or take medications that are known to cause QT prolongation. The patients with well controlled HBP can be considered to be included.
8. Pulmonary systolic pressure (PSP) of echocardiography is more than 50 mmHg, or there is clinical symptom related to pulmonary hypertension.
9. Have a history of serious cardiovascular diseases during the previous treatment of chronic myeloid leukemia with TKI, including myocardial infarction, unstable angina pectoris, severe arrhythmia and congestive heart failure.
10. Underwent autologous or allogeneic stem cell transplant.
11. CML-CP patient currently diagnosed as Complete cytogenetic remission (CCyR).
12. Have diseases with abnormal bleeding and coagulation function, or have a bleeding disorder unrelated to CML within 3 months before first dose of study drug.
13. Underwent major surgery (except minor surgical procedures, such as placement or bone marrow biopsy) with 14 days prior to the first dose of study drug.
14. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy (It is defined as a daily dose of corticosteroids less than 30 mg prednisone or the same amount of other corticosteroids within 7 days).
15. Have active nervous system (CNS) disease as evidence by cytology or pathology. In the absence of clinical CNS disease, lumbar puncture is not required.
16. History of another primary malignancies.
17. Active symptomatic infection.
18. Known to be allergic to study drug ingredients or their analogues.
19. Female patients with blood β-Human chorionic gonadotropin (HCG)positive, pregnant or lactating or expecting pregnancy during the study program.
20. Suffer from any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the research drug.

Primary outcomes:
measure: Major cytogenetic response (MCyR)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
Secondary outcomes:
measure: Complete cytogenetic response (CCyR)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Complete hematologic response (CHR)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Major molecular response (MMR)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: BCR-ABL1(IS) transcript ≤1%
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Time to response
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Duration of response
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Progression free survival (PFS)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Overall survive (OS)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Safety: adverse events (AEs), and serious AEs (SAEs)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
Other outcomes:
measure: The relationship between mutation and efficacy.
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
measure: Quality of life (QOL)
timeFrame: By the end of Cycle 24 (each cycle is 28 days)
Locations:
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
city: Shenzhen
country: China
facility: Shenzhen Second People's Hospital
state: Guandong
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Guanzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Tumor Hospital
state: Henan
city: Wuhan
country: China
facility: Union Hospital medical college Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Tongji medical college Huazhong University of Science and Technology
state: Hubei
city: Suzhou
country: China
facility: The First Hospital Affiliated of Soochow University
state: Jiangsu
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
city: Tianjin
country: China
facility: Blood Diseases Hospital Chinese Academy of Medical Sciences
Study officials:
affiliation: Peking University People's Hospital
name: Xiaojun Huang, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Peking University People's Hospital
name: Qian Jiang, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jiang Q, Li Z, Qin Y, Li W, Xu N, Liu B, Zhang Y, Meng L, Zhu H, Du X, Chen S, Liang Y, Hu Y, Liu X, Song Y, Men L, Chen Z, Niu Q, Wang H, Lu M, Yang D, Zhai Y, Huang X. Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial. J Hematol Oncol. 2022 Aug 18;15(1):113. doi: 10.1186/s13045-022-01334-z.