| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10080018 |
| E.1.2 | Term | Philadelphia positive acute lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the efficacy of ponatinib versus imatinib, administered as first-line therapy in combination with
reduced-intensity chemotherapy, in patients with newly diagnosed Ph+ ALL, as measured by the MRD-negative CR rate at the end of induction. |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
To compare the rates of EFS between the 2 cohorts
Other Secondary Objectives:
Please refer to study protocol
Exploratory objective:
To explore biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or biomarkers affecting ponatinib efficacy or safety. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
|
| E.3 | Principal inclusion criteria |
1. Male or female patients aged 18 years or older.
2. Newly diagnosed Ph+ or BCR-ABL1 positive ALL, as defined by the 2017 National Comprehensive Cancer Network guidelines.
3. Molecular assessment of BCR-ABL1 must demonstrate the presence of a p190 (ie, e1a2) or p210 (ie, e13a2 or
e14a2 [also known as b2a2 or b3a2]) transcript type.
4. Eastern Cooperative Oncology Group performance status of ≤2.
5. Clinical laboratory values as follows, within 30 days before randomization:
a) Total serum bilirubin ≤1.5× the upper limit of normal (ULN).
b) Alanine aminotransferase or aspartate aminotransferase ≤2.5× the ULN.
c) Serum creatinine ≤1.5× the ULN and estimated creatinine clearance ≥40 mL/minute (Cockcroft-Gault formula).
d) Serum lipase and amylase <1.5× the ULN.
6. Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram, defined as QTcF of
≤450 ms in males or ≤470 ms in females.
7. 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 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
d) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
(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.)
8. 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 subject.
(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.)
9. 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.
10. Willingness and ability to comply with scheduled visits and study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Patients with a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid
leukemia.
2. Prior/current treatment with any systemic anticancer therapy and/or
radiotherapy for cancer, with the exception of an optional prephase therapy, which should be discussed with the
sponsor’s medical monitor/designee.
3. Treatment with any investigational products within 30 days before randomization or 6 half-lives of the agent,
whichever is longer.
4. 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)
5. 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.
6. Active serious infection requiring antibiotics within 14 days before the first dose of study drug.
7. Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or BM biopsy are not exclusionary criteria).
8. Ongoing or active systemic infection, known seropositive HIV, or known active hepatitis B or C infection.
9. History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis.
10. Uncontrolled hypertriglyceridemia (tg >450 mg/dL).
11. 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 excluded if they have not undergone complete resection.
12. 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.
13. Clinical manifestations of CNS or extramedullary involvement with ALL
14. Autoimmune disease with potential CNS involvement.
15. Known significant neuropathy of Grade ≥2 severity.
16. 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 minute).
e) Uncontrolled HTN (systolic blood pressure [BP] ≥150 mmHg and/or diastolic BP
≥90 mmHg). Patients with Stage 2 HTN (systolic BP ≥140 mmHg 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.
f) Any history of myocardial infarction, unstable angina, coronary artery disease, cerebrovascular accident,
ischemic stroke, or transient ischemic attack.
g) History of congestive heart failure (NYHA class III or IV) 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.
17. Poorly controlled diabetes, defined as glycosylated hemoglobin values of >7.5%. Patients with preexisting,
well-controlled diabetes are not excluded.
18. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
19. Ongoing uncontrolled nausea or vomiting of any severity.
20. Diarrhea of Grade >1, based on the NCICTC for Adverse Events categorization.
21. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime
sleepiness, such as severe chronic obstructive pulmonary disease.
22. Have a significant bleeding disorder unrelated to ALL.
23. Life-threatening illness unrelated to cancer, such as severe CNS, pulmonary, renal, or hepatic disease unrelated to cancer.
24. Female patients who are lactating or breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on D1 before the first dose of study drug is administered.
25. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
26. Admission or evidence of illicit drug or alcohol abuse. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary efficacy endpoint: MRD-negative CR (BCR-ABL/ABL1 ≤0.01% and meeting criteria for CR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
EFS is defined as the dates of randomization until death due to any cause or failure to achieve MRD-negative CR by end of induction or relapse from CR.
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).
CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.
ORR is defined as CR + CRi.
Duration of MRD-negative CR is defined as 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.
Duration of CR is defined as interval between the first assessment at which the criteria for CR are met until the earliest date at which relapse from CR occurs.
Time to treatment failure is defined as time to being off study randomized treatment (except for hematopoietic stem cell transplantation [HSCT] without loss of MRD-negative CR) due to both safety and/or loss of efficacy benefit reasons.
Molecule response is assessed by 3-Log Reduction (MR3), Molecular Response 4-Log Reduction (MR4) and Molecular Response 4.5-Log Reduction (MR4.5).
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.
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.
On-study participants with or without HSCT will be evaluated. OS is defined as the interval between the first dose date of study drug and death due to any cause, censored at the last contact date when the participant was alive.
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.
OS is defined as interval between the first dose date of study drug and death due to any cause, censored at the last contact date when the participant was alive.
Exploratory end point :
Biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or biomarkers affecting ponatinib efficacy or safety. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•EFS: Baseline up to 3 years
•% of Pts with CR and CRi: End of C1 (approximately 1 month), C2
(approximately 2 months) and C3 (approximately 3 months)
•% of Pts with Molecular Response: End of cycle 1 (approximately 1
month), cycle 2 (approximately 2 months) and cycle 3: approximately 3
months
•Percentage of PIF: Up to 3 months
•% of Participants with ORR: Up to 3 months
•Duration of MRD-Negative CR: Up to 5 years
•Duration of CR: Up to 5 years
•Time to Treatment Failure: Every year after 3 years up to 5 years
•% of Pts with MR4.5 Including Best Response: Up to 5 years
•Duration of MR4.5: Up to 5 years
•% of On-Study Pts with OS: Every year after 3 years up to 5 years
•% of On-Study Pts with Relapse From CR: Every year after 3 years up to
5 years
•OS:Up to 5 years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belarus |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Finland |
| France |
| Greece |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be considered completed when the death of all patients has been recorded or when the study has been terminated by the sponsor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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