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

Inclusion criteria

• {"criterion_text":"- Male or female patients aged 18 years or older. • In Argentina, male or female patients 40 years and older. • In South Korea, male or female patients who are either: a) aged ≥18 through <65 years with comorbidities and/or poor functional status that, after discussion/agreement with the medical monitor/designee, are considered to make the patient unfit for any intensive therapy, or b) aged ≥65 years.\n- Newly diagnosed Ph+ or BCR-ABL1 positive ALL, as defined by the 2017 National Comprehensive Cancer Network guidelines.\n- Eastern Cooperative Oncology Group performance status of ≤2.\n- Clinical laboratory values as follows, within 30 days before randomization: a) Total serum bilirubin ≤1.5× the upper limit of normal (ULN), unless due to Gilbert's syndrome. b) Alanine aminotransferase (ALT) or aspartate aminotransferase ≤2.5× the ULN. c) Serum creatinine ≤1.5× the ULN and estimated creatinine clearance ≥ 30 mL/minute (Cockcroft-Gault formula). d) Serum lipase <1.5× the ULN.\n- Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram, defined as QTcF of ≤450 ms in males or ≤ 470 ms in females.\n- Female patients who: a) Are postmenopausal for at least 1 year before the screening visit, OR b) Are surgically sterile, OR c) If they are of childbearing potential, agree to practice 1 highly effective method of contraception (such as any form of hormonal contraception, eg, birth control pills or hormonal intra-uterine device [IUD]) and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 1 month after the last dose of study drug or a longer period per any local regulation, eg, 35 days for patients in France), OR d) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)\n- Male patients, even if surgically sterilized (ie, status postvasectomy), who: a) Agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR b) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)\n- Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.\n- Willingness and ability to comply with scheduled visits and study procedures"}

Exclusion criteria

• {"criterion_text":"- Patients with a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia\n- Uncontrolled hypertriglyceridemia (tg >450 mg/dL)\n- Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection\n- History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis\n- Clinical manifestations of CNS or extramedullary involvement with ALL other than lymphadenopathy or hepatosplenomegaly\n- Autoimmune disease with potential CNS involvement\n- Known significant neuropathy of Grade≥2 severity\n- Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or peripheral vascular disease, or history of or active VTE disease, including, but not restricted to: a) Complete left bundle branch block b) Right bundle branch block plus left anterior hemiblock or bifascicular block c) History of or presence of clinically significant ventricular or atrial tachyarrhythmias d) Clinically significant resting bradycardia (<50 beats per min) e) Uncontrolled HTN (systolic blood pressure [BP] ≥150mmHg and/or diastolic BP ≥90mmHg). Patients with Stage 2 HTN (systolic BP ≥ 140mmHg and/or diastolic BP ≥90 mmHg) should be under treatment at study entry per the current AHA guidelines to ensure BP control. Patients requiring 3 or more antihypertensive medications should have controlled HTN for the past 6 months. Isolated elevation(s) of systolic and/or diastolic BP during screening are not exclusionary f) Any history of myocardial infarction, unstable angina, coronary artery disease, cerebrovascular accident, ischemic stroke, or transient ischemic attack. Note: patients with any history of these events, whether considered clinically significant or not, are excluded g) History of congestive heart failure or left ventricular ejection fraction <40%, within 6 months before randomization h) Symptomatic peripheral vascular disease or history of infarction, including visceral infarction i) History of any revascularization procedure, including the placement of a stent j) Patients with documented significant pleural or pericardial effusions unless thought to be secondary to leukemia k) Any history of venous thromboembolism, including but not limited to deep venous thrombosis or pulmonary embolism within 6 months before randomization\n- Poorly controlled diabetes, defined as glycosylated hemoglobin values of >7.5%. Patients with preexisting, well-controlled diabetes are not excluded\n- Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing\n- Ongoing uncontrolled nausea or vomiting of any severity\n- Prior/current treatment with any systemic anticancer therapy and/or radiotherapy for ALL, with the exception of an optional prephase therapy or chemotherapy induction (no more than 1 cycle), which should be discussed with the sponsor's medical monitor/designee\n- Have a significant bleeding disorder unrelated to ALL\n- Life-threatening illness unrelated to cancer, such as severe CNS, pulmonary, renal, or hepatic disease unrelated to cancer\n- Female patients who are lactating or breastfeeding or have a positive serum pregnancy test during the screening period or have a positive urine pregnancy test on D1 before the first dose of study drug is administered\n- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol\n- Admission or evidence of illicit drug or alcohol abuse\n- Treatment with any investigational products within 30 days before randomization or 6 half-lives of the agent, whichever is longer\n- Currently taking drugs that are known to have a risk of causing prolonged QTc or TDP (unless these can be changed to acceptable alternatives or discontinued)\n- Taking any medications or herbal supplements that are known to be strong inhibitors or strong inducers of cyt P450 3A4 within at least 14 days before the first dose of study drug\n- Uncontrolled active serious infections that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol\n- Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or BM biopsy are not exclusionary criteria)\n- Known seropositive HIV, known active hepatitis B or C infection\n- History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis"}

Primary endpoints

• {"endpoint_text":"- Primary efficacy endpoint: MRD-negative CR (BCR-ABL/ABL1 ≤0.01% and meeting criteria for CR)","definition_or_measurement_approach":"MRD-negative CR defined as BCR-ABL/ABL1 ≤0.01% and meeting criteria for CR"}

Secondary endpoints

• {"endpoint_text":"- EFS is defined as the dates of randomization until death due to any cause or failure to achieve CR by end of induction or relapse from CR.","definition_or_measurement_approach":"EFS = time from randomization until death from any cause, failure to achieve CR by end of induction, or relapse from CR"}
• {"endpoint_text":"- CR is defined as meeting all of the following for at least 4 weeks (ie, no recurrence): 1. No circulating blasts and <5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC >1000/μl (or >1.0*10^9/L). 5. Platelets >100,000/μl (or >100*10^9/L).","definition_or_measurement_approach":"CR requires all listed hematologic and disease criteria sustained for at least 4 weeks"}
• {"endpoint_text":"- CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.","definition_or_measurement_approach":"CRi is CR except platelet count and/or ANC criteria not met"}
• {"endpoint_text":"- ORR is defined as CR + CRi.","definition_or_measurement_approach":"ORR = CR + CRi"}
• {"endpoint_text":"- Duration of MRD-negative CR is defined as the interval between the first assessment at which the criteria for MRD-negative CR are met until the earliest date at which loss of MRD negativity or relapse from CR occurs.","definition_or_measurement_approach":"Interval from first MRD-negative CR assessment until loss of MRD negativity or relapse"}
• {"endpoint_text":"- Duration of CR is defined as the interval between the first assessment at which the criteria for CR are met until the earliest date at which relapse from CR occurs.","definition_or_measurement_approach":"Interval from first CR assessment until relapse"}
• {"endpoint_text":"- Time to treatment failure is defined as time to end of study-randomized treatment (except for hematopoietic stem cell transplantation [HSCT] without loss of MRD-negative CR) due to safety and/or efficacy reasons.","definition_or_measurement_approach":"Time from randomization to end of randomized study treatment for safety/efficacy reasons (HSCT exception as noted)"}
• {"endpoint_text":"- Molecule response is assessed by 3-Log Reduction (MR3), Molecular Response 4-Log Reduction (MR4) and Molecular Response 4.5-Log Reduction (MR4.5).","definition_or_measurement_approach":"Molecular responses assessed as MR3, MR4, MR4.5 (log-reduction levels of BCR-ABL)"}
• {"endpoint_text":"- PIF is defined as participants who received treatment for chromosomepositive acute lymphoblastic leukemia (ALL) but never achieved CR or CRi by the end of induction. PIF is not limited by the number of unsuccessful treatments; this disease status only applies to recipients who have never been in CR or CRi.","definition_or_measurement_approach":"Participants treated for Ph+ ALL who never achieved CR or CRi by end of induction"}
• {"endpoint_text":"- MR4.5 is molecular response 4.5-log reduction (≤0.0032% BCRABL1/ABL1), or undetectable BCR-ABL1 transcripts in cDNA with ≥ 32,000 ABL1 transcripts.","definition_or_measurement_approach":"MR4.5 defined as ≤0.0032% BCR-ABL1/ABL1 or undetectable BCR-ABL1 with ≥32,000 ABL1 transcripts"}
• {"endpoint_text":"- On-study participants with or without HSCT will be evaluated. OS is defined as the interval between randomization and death due to any cause, censored at the last contact date when the participant was alive.","definition_or_measurement_approach":"OS = time from randomization to death from any cause, censored at last contact alive"}
• {"endpoint_text":"- On-study participants with or without HSCT will be evaluated. Relapse from CR is defined as reappearance of blasts in the blood or BM (>5%) or in any extramedullary site after a CR.","definition_or_measurement_approach":"Relapse from CR = reappearance of blasts in blood or BM (>5%) or any extramedullary site after CR"}
• {"endpoint_text":"- OS is defined as interval between randomization and death due to any cause, censored at the last contact date when the participant was alive.","definition_or_measurement_approach":"OS definition (duplicate): time from randomization to death from any cause, censored at last contact alive"}

Other endpoints

• {"endpoint_text":"- Exploratory end point: Biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or biomarkers affecting ponatinib efficacy or safety.","definition_or_measurement_approach":"Exploratory biomarker analyses of disease sensitivity/resistance and biomarkers affecting ponatinib efficacy/safety"}

Austria

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

06-10-2025

Processing Time Days

537

Number Of Sites

2

Number Of Participants

6

Poland

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

06-10-2025

Processing Time Days

537

Number Of Sites

2

Number Of Participants

7

Italy

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

30-09-2025

Processing Time Days

531

Number Of Sites

11

Number Of Participants

38

France

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

02-10-2025

Processing Time Days

533

Number Of Sites

4

Number Of Participants

10

Spain

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

30-09-2025

Processing Time Days

531

Number Of Sites

4

Number Of Participants

25

Greece

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

31-10-2025

Processing Time Days

562

Number Of Sites

3

Number Of Participants

5

Primary sponsor

Full Name

Takeda Development Center Americas Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD International Holdings LLC

Responsibilities

[{"code":4}]

Name

Icon Clinical Research Limited

Responsibilities

[{"code":1},{"code":12},{"code":2},{"code":6},{"code":8}]

Name

PRA Hellas CRO A.E.

Responsibilities

[{"code":1},{"code":12},{"code":15,"value":"site contract negotiations and payments"},{"code":2},{"code":8}]

Third parties

• {"country":"Belgium","full_name":"PPD International Holdings LLC","duties_or_roles":"[{\"code\":4}]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Molecularmd Corp.","duties_or_roles":"[{\"code\":15,\"value\":\"Biomarker analysis\"},{\"code\":4}]","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"[{\"code\":1},{\"code\":12},{\"code\":2},{\"code\":6},{\"code\":8}]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"[{\"code\":15,\"value\":\"Cardiovascular Endpoint Adjudication Committee\"}]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Q Squared Solutions LLC","duties_or_roles":"[{\"code\":1},{\"code\":15,\"value\":\"PK Samples\"},{\"code\":5}]","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Greece","full_name":"PRA Hellas CRO A.E.","duties_or_roles":"[{\"code\":1},{\"code\":12},{\"code\":15,\"value\":\"site contract negotiations and payments\"},{\"code\":2},{\"code\":8}]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Yprime LLC","duties_or_roles":"[{\"code\":7}]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Biopier Inc.","duties_or_roles":"[{\"code\":10}]","organisation_type":"Pharmaceutical company"}