| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| acute lymphoblastic leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Phase 1
- To determine the RP2D of ponatinib (tablet and AAF) in combination with chemotherapy.
Phase 2
- To determine the efficacy of ponatinib in combination with chemotherapy as measured by the rate of CR at the end of the reinduction block. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
- To define and describe the phase 1 efficacy of ponatinib (tablet and AAF) in combination with chemotherapy.
Phase 2
- Ph+ ALL only: To describe the proportion of patients who achieved CR at the end of consolidation
- Ph+ ALL only: To describe the proportion of patients with minimal residual disease (MRD) status <0.01% among those who achieved CR at the end of each treatment block.
- To determine the proportion of patients who relapsed or progressed.
- To determine event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) at 6 months, 1 year, 18 months, 2 years, and 3 years.
- To determine duration of response (for CR).
- To determine the proportion of patients who underwent hematopoietic stem cell transplantation (HSCT)
following study treatment.
Other Secondary Objectives (Phase 1/2 PK and Safety) can be found in the study protocol (section 5.1.2). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1 cohort 1 (enrollment and treatment completed) eligibility criteria at the time of enrollment for patients to be administered ponatinib as the tablet formation:
- Patients must have a body weight ≥30 kg.
- Patients must be able to swallow solid oral dosage forms.
Phase 1 cohort 2 eligibility criteria at the time of enrollment:
- Patients must be aged ≥1 year and have a body weight of at least 5 kg.
Each patient must meet all the following inclusion criteria to be enrolled in the study for phase 1 and phase 2.
1. Diagnosis: Patients must have a diagnosis of Ph+ ALL, Ph+ MPAL or Ph-like ALL with:
a. Involvement of bone marrow (BM) with ALL, including one of the following:
i. M2 BM (5%-24% lymphoblasts): by morphology with confirmatory testing consisting of at least one of the following: flow cytometry lymphoblasts ≥5%, or BCR-ABL1 fluorescence in situ hybridization, or ≥10^-2 leukemic clone identified by immunoglobulin heavy chain–T-cell receptor polymerase chain reaction, OR
ii. M3 BM (≥25% lymphoblasts): by morphology, OR
iii. Patients with combined BM (as defined above) and extramedullary disease.
b. Evidence of Ph+ ALL, MPAL, or Ph-like ALL:
i. Definite evidence of BCR-ABL1 fusion (Ph) for Ph+ ALL and MPAL, OR
ii. Definite evidence of Ph-like ALL with targetable kinase-activating lesions involving any of the following kinase genes: ABL1, ABL2, CSF1R, and PDGFRB.
Ph-like ALL diagnosis requires the identification of specified targetable kinase-activating lesions preferably by RNA sequencing or by
alternative accredited method used by the site. Referring institution’s laboratory results will be accepted for diagnosis and study enrollment. No confirmation by a sponsor central laboratory is required.
c. Disease status
i. For non-US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at least 1 prior therapy that contained a BCR-ABL1–targeted TKI, OR
ii. Have a BCR-ABL1 T315I mutation irrespective of relapse, resistance/intolerance, or transplant status and irrespective of any prior TKI use. Referring institution’s laboratory results will be accepted for enrollment; however, the mutation needs to be confirmed by the central laboratory. If the mutational status is not concordant, the patient will be withdrawn from the study and excluded from analyses for RP2D and efficacy, but included for safety.
Other inclusion criteria can be found in the study protocol (section 7.1). |
|
| E.4 | Principal exclusion criteria |
1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell leukemia.
2. A history or current diagnosis of CML.
3. Diagnosis of ALL, MPAL, or Ph-like ALL (US only) with targetable kinase-activating lesions after treatment with cytotoxic therapy for another cancer.
4. Diagnosis of another concurrent primary malignancy.
5. Clinically significant cardiovascular disease, including but not limited to:
a. Any history of myocardial infarction (MI) or unstable angina.
b. History of or presence of heart block, and/or clinically significant ventricular or atrial
arrhythmias.
c. Uncontrolled hypertension, defined as persistent elevation of systolic and/or diastolic blood pressures to ≥95th percentile based on age, sex, and height percentiles despite appropriate antihypertensive management.
6. Current systemic use of drug(s) that are known to have a risk of causing prolonged corrected
QT interval (QTc) or torsades de pointes unless drug(s) can be changed to acceptable
alternatives (ie, an alternate class of agents that do not affect the cardiac conduction system) or the patient can safely discontinue the drug(s).
7. Uncontrolled hypertriglyceridemia (triglycerides ≥450 mg/dL).
8. Current systemic use of any medications or herbal supplements that are known to be strong inhibitors or strong inducers of CYP3A within 7 days before the first dose of study drug.
9. Previous treatment with ponatinib.
10. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or
immunotherapy while patient is on study treatment.
11. Known allergy or contraindications to any of the drugs (active or excipient) used in the study.
12. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption of ponatinib.
13. Patients with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome.
14. Patients with Down syndrome.
15. Patients with uncontrolled systemic infection, known laboratory and/or clinical evidence of active infection with HIV, hepatitis B, or hepatitis C.
16. Patients with pre-existing significant CNS pathology including: history of severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination /movement disorder, or autoimmune disease with CNS involvement are not eligible.
17. 17. Patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible. (Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits and causative factor(s) have resolved.)
18. Uncontrolled seizure disorder. (Patients with seizure disorders that do not require antiepileptic drugs, or are well controlled with stable doses of antiepileptic drugs are eligible.)
19. History of severe coagulopathy or cardiovascular or peripheral vascular events.
20. Any condition or illness that, in the opinion of the investigator or sponsor, would compromise patient safety or interfere with the evaluation of the safety or efficacy of ponatinib.
21. Admission or evidence of illicit use, drug abuse, or alcohol abuse.
22. Pregnancy and breastfeeding exclusions:
a. Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been noted
for several of the study treatments. A pregnancy test is required for female patients of childbearing potential.
b. Lactating women who plan to breastfeed their infants.
23. Treatment with live attenuated vaccinations within 30 days prior to initiation of study treatment regimen. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
- RP2D of ponatinib (tablet and AAF) in combination with chemotherapy.
Phase 2
- CR at the end of the reinduction block. CR is defined as <5% blasts in bone marrow, normal maturation of all cellular components in the bone marrow, no evidence of extramedullary disease, absolute neutrophil count (ANC) >1000/μL, and platelet count of >100,000/μL |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of the reinduction block, both prior to and following ponatinib treatment.
|
|
| E.5.2 | Secondary end point(s) |
Phase 1
- CR at the end of the reinduction block. CR is defined as <5% blasts in bone marrow, normal maturation of all cellular components in the bone marrow, no evidence of extramedullary disease, ANC >1000/μL, and platelet count of >100,000/μL.
Phase 2
- Ph+ ALL only: Proportion of patients who achieved CR at the end of consolidation
- Ph+ ALL only: Proportion of patients with MRD-negative status (<0.01%) among those who achieved CR at the end of each treatment block.
- Proportion of patients who relapsed or progressed.
- EFS, PFS, and OS at 6 months, 1 year, 18 months, 2 years, and 3 years
- Duration of response (for CR).
- Proportion of patients who underwent HSCT following study treatment.
Phase 1 PK Endpoint
- Summary statistics of ponatinib PK parameters including maximum observed plasma concentration (Cmax), time of first occurrence of Cmax (Tmax), and area under the plasma concentration–time curve from time 0 to the time of the last quantifiable concentration (AUClast).
Phase 1 and Phase 2 Safety Endpoint
- Adverse events (AEs), serious adverse events (SAEs), arterial occlusive events (AOEs), venous thrombotic/embolic events (VTEs), and any other AEs of special interest (AESIs). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of the reinduction block, both prior to and following ponatinib treatment. |
|
| 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 | No |
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| safety, tolerability, PK and efficacy of the IP + chemotherapy in pediatric patients |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard of care / Backbone therapy |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Brazil |
| China |
| Korea, Republic of |
| Mexico |
| United Kingdom |
| United States |
| Czechia |
| France |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
|
| 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
|
| Last Subject Last Visit (follow-up) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| 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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