Olverembatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)

Inclusion criteria

• {"criterion_text":"- ≥ 18 years old.\n- Meet 2016 WHO classification and diagnostic criteria for Philadelphia chromosome- or BCR/ABL1-positive Ph+ ALL. Patients must be newly diagnosed with Ph+ ALL and haven't received systemic anti-leukaemia therapy previously, except for hydroxycarbamide treatment, vincristine treatment no more than once, and steroids therapy for no more than 28 days.\n- Life expectancy of ≥ 3 months.\n- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.\n- Adequate organ function as indicated below: • Hepatic function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × Upper Limit of Normal (ULN), serum total bilirubin ≤ 1.5 × ULN (and for patients with Gilbert’s syndrome serum total bilirubin ≤ 3.0 x ULN); • Renal function: Serum creatinine ≤ 1.5 × ULN; or 24 h creatinine clearance (CrCL) must be ≥ 50 mL/min (Cockcroft-Gault formula) when serum creatinine is > 1.5 × ULN; • Coagulation: International normalized ratio (INR), activated partial thromboplastin time (APTT), and prothrombin time (PT) all ≤ 1.5 × ULN; • Cardiac function index: Left ventricular ejection fraction (LVEF) > 50%; • Troponin I or T ≤ ULN; • QT interval corrected using the Fridericia's formula (QTcF) on electrocardiogram (ECG): QTcF ≤ 450 ms in males or ≤ 470 ms in females.\n- Males and females of childbearing potential (only postmenopausal women who have not menstruated for at least 12 months or are surgically sterilized can be considered infertile) and their partners voluntarily take effective contraceptive measures throughout the treatment and until at least 4 months after the last dose of the study drug. Male patients are not allowed to donate sperm.\n- Female patients of childbearing potential have negative serum pregnancy test results within 7 days prior to the first dose\n- Patients must be able to understand and voluntarily sign a written informed consent form that has been approved by the Ethics Committee (EC) and voluntarily complete study procedures and follow-up examinations"}

Exclusion criteria

• {"criterion_text":"- Prior history of chronic myelocytic leukemia and diagnosis of chronic myelocytic leukemia in lymphoid blast phase (BP)\n- Any disease or medical condition that is unstable or might affect the patient’s safety or study compliance, such as uncontrolled hypertension, uncontrolled diabetes mellitus, active hemorrhage (within 3 months), severe respiratory system disorder (e.g., chronic obstructive pulmonary disease, severe asthma, etc.), significant renal, nervous, endocrine, metabolic, immune, hepatic, digestive diseases, and mental diseases, etc.\n- Use of drugs that are known to possibly cause prolonged ECG QT\n- Active fungal/bacterial/viral infection that requires systemic treatment, including but not limited to human immunodeficiency virus (HIV), active viral hepatitis B and hepatitis C, known active COVID-19 (those who have received COVID-19 vaccine or other attenuated live vaccine more than 28 days before enrollment are acceptable).\n- Diseases seriously affect oral administration and absorption of drugs or those who have active peptic ulcer\n- Contraindications to glucocorticoids and unsuitable for participating in the study, at the discretion of the investigator\n- Hemorrhagic disorder unrelated to the tumor: such as congenital hemorrhagic disorder (e.g., angiohaemophilia von Willebrand disease), acquired hemorrhagic disorder diagnosed within 1 year (e.g., acquired factor VIII inhibitor), etc.\n- A major surgery within 14 days prior to the first dose of the study drug (except for minor surgeries such as bone marrow biopsy and deep vein catheterization) or those who haven’t fully recovered from previous surgeries, at the discretion of the investigator.\n- Hypersensitivity to ingredients, excipients or analogues of drugs used in the study\n- Females who are pregnant, breastfeeding, or planning to become pregnant during the study or within 4 months of Olverembatinib after the last dose\n- Other malignancies within 2 years prior to enrollment, with the exception of: adequately treated cervical carcinoma in situ or breast carcinoma in situ; completely excised skin basal cell carcinoma or localized squamous cell carcinoma of the skin. It is necessary to discuss with the Sponsor for patients with a history of localized malignancy that has been cured by excision (or other methods) which will not affect safety and efficacy evaluation of the study, at the discretion of the investigator.\n- Clinical manifestations of central nervous system (CNS) leukemia or ALL extramedullary infiltration, except lymphadenopathy or hepatosplenomegaly\n- Any symptom or disease that may compromise patients' safety or interfere with the efficacy and safety assessment of the study drug, or any other situation or condition unsuitable for participating in the study. In special circumstances, a decision will be made after the investigator discusses with the Sponsor\n- Previous or current clinical CNS diseases, e.g., epilepsy, epileptic seizure of children or adults, paresis, alogia, apoplexy, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or mental aberration\n- Autoimmune disorders that may involve CNS.\n- Use of anticoagulants and/or antiplatelet drugs at therapeutic doses, but those using low-dose anticoagulants for keeping the central line patent are acceptable.\n- Use of a drug for other concomitant diseases which interacts with the study drug (e.g., strong CYP2C9 inducers or inhibitors and moderate to strong CYP3A4 inducers or inhibitors) within 7 days or 5 half-lives prior to the first dose (whichever is shorter).\n- Presence of any of the following heart injuries at screening: a. New York Heart Association (NYHA) Class III to IV; b. Uncontrolled angina, congestive cardiac failure or myocardial infarction within 6 months prior to the first dose; c. Second-degree type II, third-degree atrioventricular (AV) block or PR interval > 250 ms, etc.; d. Various factors that have a potential to increase the risk of prolonged QTcF or arrhythmia, such as cardiac failure, hypopotassaemia, congenital long QT syndrome, and a family history of sudden death of unknown cause before the age of 40 years in a first-degree relative;\n- Any venous thromboembolism within 6 months before randomization, including but not limited to deep vein thrombosis (DVT) or lung embolism\n- Use of prohibited drugs within 7 days or 5 half-lives prior to the first dose (whichever is shorter);"}

Primary endpoints

• {"endpoint_text":"- MRD-negative CR rate at the end of induction (EOI): MRD-negativity is defined as BCR-ABL/ABL1 ≤ 0.01% measured centrally by reverse transcription qPCR. CR is defined as meeting the following criteria: ①No circulating blasts; No extramedullary disease (i.e., no lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass or CNS involvement);","definition_or_measurement_approach":"MRD-negativity defined as BCR-ABL/ABL1 ≤ 0.01% measured centrally by reverse transcription qPCR. CR defined by absence of circulating blasts and absence of extramedullary disease as listed; central molecular testing for MRD."}
• {"endpoint_text":"- Normal maturation of all cellular components in the BM and less than 5% blasts in the bone marrow;","definition_or_measurement_approach":"Assessed by bone marrow evaluation showing normal maturation of cellular components and <5% blasts in bone marrow."}
• {"endpoint_text":"- absolute neutrophil count (ANC) ≥ 1.0 × 109/L","definition_or_measurement_approach":"Measured by peripheral blood complete blood count (CBC); ANC ≥ 1.0 × 10^9/L."}
• {"endpoint_text":"- platelet counts ≥ 100 × 109/L","definition_or_measurement_approach":"Measured by peripheral blood CBC; platelet count ≥ 100 × 10^9/L."}
• {"endpoint_text":"- no relapse within 4 weeks","definition_or_measurement_approach":"Absence of relapse within 4 weeks after assessment; relapse defined per study relapse criteria (reappearance of blasts in blood or bone marrow or extramedullary disease)."}

Secondary endpoints

• {"endpoint_text":"- Event‑free survival (EFS): EFS is the key secondary endpoint. EFS is defined as the time from study randomization to the date of treatment failure (ITF), relapse from CR, or death from any cause, whichever comes first. ITF is defined as failure to achieve CR during induction period (i.e., considering CRi responses treatment failures).","definition_or_measurement_approach":"EFS measured from randomization to treatment failure (failure to achieve CR during induction), relapse from CR, or death; time-to-event analysis."}
• {"endpoint_text":"- Overall response rate (ORR): ORR is defined as complete response (CR), CR with partial hematologic recovery (CRh) and CR with incomplete hematologic recovery (CRi). (1) CRh is defined as hematologic complete remission with partial hematologic recovery and meeting all criteria for CR except platelet count and ANC (ANC > 0.5 × 109/L and platelet counts > 50 × 109/L)","definition_or_measurement_approach":"ORR includes CR, CRh, CRi per hematologic and marrow criteria; CRh defined as above; responses assessed by standard hematologic and marrow assessments."}
• {"endpoint_text":"- CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count or ANC (platelet counts < 100 × 109/L and ANC ≥ 1.0 × 109/L, or platelet counts ≥ 100 × 109/L and ANC < 1.0 × 109/L)","definition_or_measurement_approach":"CRi determined by CBC and marrow showing criteria listed; captured as part of response assessments."}
• {"endpoint_text":"- Duration of MRD-negative CR: The interval from the date when MRD-negative CR criteria are first met upon evaluation to the date of molecular relapse from MRD-negativity, or relapse after CR, or to the date of leukemia-related death.","definition_or_measurement_approach":"Time from first documented MRD-negative CR (central BCR-ABL/ABL1 ≤0.01%) to molecular relapse, relapse after CR, or leukemia-related death."}
• {"endpoint_text":"- Duration of CR, CRh or CRi: The interval from the date when CR, CRh, or CRi criteria are first met upon evaluation to the earliest date of relapse after CR, CRh or CRi.","definition_or_measurement_approach":"Time-to-event duration measured from first documented response to earliest relapse date."}
• {"endpoint_text":"- Time to MRD-negative CR: The interval from the date of randomization to the date when MRD-negative CR first met upon evaluation","definition_or_measurement_approach":"Time from randomization to first documented MRD-negative CR (central molecular measurement)."}
• {"endpoint_text":"- Time to CR, CRh or CRi: The interval from the date of randomization to the date when CR, CRh or CRi criteria are first met upon evaluation","definition_or_measurement_approach":"Time from randomization to first documented hematologic response (CR/CRh/CRi)."}
• {"endpoint_text":"- Time to treatment failure: The time to discontinuation of randomized study treatment (excluding HSCT performed when MRD-negativity is maintained) for patients due to safety concerns and/or the loss of efficacy benefit","definition_or_measurement_approach":"Time from randomization to discontinuation of randomized study treatment for safety or loss of efficacy (excluding HSCT in MRD-negative patients)."}
• {"endpoint_text":"- Progression‑free survival (PFS): PFS is defined as the date of randomization to the first documented occurrence of the following events: • Progressive disease: An increase of at least 25% in the absolute number of circulating or bone marrow blasts or development of extramedullary disease • Disease relapse: Reappearance of blasts in the blood or bone marrow (>5%) or in any extramedullary site after a CR/CRh/CRi • Death due to any cause","definition_or_measurement_approach":"PFS measured from randomization to documented progression (≥25% increase in blasts or extramedullary disease), relapse (>5% blasts) after CR/CRh/CRi, or death; time-to-event analysis."}
• {"endpoint_text":"- OS: The interval from the date of randomization to the date of death due to any cause (to the last contact date if the patient is still alive).","definition_or_measurement_approach":"Overall survival measured from randomization to death from any cause (censor at last contact if alive)."}

Hungary

Earliest CTIS Part Ii Submission Date

06-06-2025

Latest Decision Or Authorization Date

07-07-2025

Processing Time Days

31

Number Of Sites

1

Number Of Participants

4

France

Earliest CTIS Part Ii Submission Date

03-06-2025

Latest Decision Or Authorization Date

01-07-2025

Processing Time Days

28

Number Of Sites

7

Number Of Participants

11

Romania

Earliest CTIS Part Ii Submission Date

16-06-2025

Latest Decision Or Authorization Date

07-07-2025

Processing Time Days

21

Number Of Sites

4

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

19-06-2025

Latest Decision Or Authorization Date

04-07-2025

Processing Time Days

15

Number Of Sites

8

Number Of Participants

16

Bulgaria

Earliest CTIS Part Ii Submission Date

06-06-2025

Latest Decision Or Authorization Date

07-07-2025

Processing Time Days

31

Number Of Sites

1

Number Of Participants

4

Czechia

Earliest CTIS Part Ii Submission Date

17-06-2025

Latest Decision Or Authorization Date

04-07-2025

Processing Time Days

17

Number Of Sites

5

Number Of Participants

16

Spain

Earliest CTIS Part Ii Submission Date

11-06-2025

Latest Decision Or Authorization Date

02-07-2025

Processing Time Days

21

Number Of Sites

10

Number Of Participants

16

Primary sponsor

Full Name

Ascentage Pharma Group Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Iqvia Biotech LLC

Responsibilities

Processing of SAEs in safety database

Name

Iqvia Biotech Limited

Name

Icon Laboratory Services Inc.

Responsibilities

Central Lab – Kits/Logistics (PK/PD)

Name

Perceptive Informatics Inc.

Name

Frontage Laboratories Inc.

Responsibilities

4

Third parties

• {"country":"United States","full_name":"Molecularmd Corp.","duties_or_roles":"Sample Storage","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Almac Clinical Services Limited","duties_or_roles":"IP Depot","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Taxi Travel Ticket S.L.","duties_or_roles":"Patient Reimbursement","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Icon Laboratory Services Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Iqvia Biotech Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Frontage Laboratories Inc.","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Icon Laboratory Services Inc. (duplicate entry for central lab role)","duties_or_roles":"Central Lab – Kits/Logistics (PK/PD)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Iqvia Biotech LLC","duties_or_roles":"Processing of SAEs in safety database","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc. (duplicate)","duties_or_roles":"3","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Novasco","duties_or_roles":"Patient Reimbursement","organisation_type":"Pharmaceutical company"}
• {"country":"China","full_name":"Clinchoice Medical (Tianjin) Co. Ltd.","duties_or_roles":"6","organisation_type":"Pharmaceutical company"}