The purpose of the study is to determine the recommended phase 2 dose (RP2D) of ponatinib
(tablet and age-appropriate formulation [AAF]) in combination with chemotherapy in Phase 1
and the efficacy of ponatinib in combination with chemotherapy as measured by the rate of
complete remission (CR) at the end of the reinduction block at the RP2D.
The drug being tested in this study is called ponatinib. Ponatinib is being tested to treat
pediatric population who have Philadelphia chromosome-positive (Ph+) acute lymphoblastic
leukemia (ALL) who have relapsed or are resistant or intolerant to a prior tyrosine kinase
inhibitor (TKI)-containing therapy, or who have the T315I mutation.
The study will enroll approximately 68 patients. Participants will be assigned to a treatment
group either in phase 1 or phase 2. Participants unable to swallow the ponatinib tablets will
receive the age-appropriate formulation, minitablets:
• Ponatinib + Chemotherapy
All participants will be asked to take ponatinib once daily. In phase 1 ponatinib will be
administered in combination with a chemotherapy backbone to determine the recommended phase 2
dose (RP2D) of ponatinib. In both phase 1 and phase 2, treatment consists of two 35-day
blocks of therapy (reinduction block and consolidation block). Each block will include 29
days of treatment of daily ponatinib and a chemotherapy backbone regimen followed by a rest
period from chemotherapy for a minimum of 6 days consisting of daily ponatinib only.
This is a multi-center trial and will be conducted worldwide. The overall time to participate
in this study is 36 months. Participants will make multiple visits to the clinic, and may be
contacted by telephone in follow-up after treatment.
Inclusion Criteria:
1. Have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotype acute
leukemia (MPAL) with definite evidence of breakpoint cluster region- Abelson 1
(BCR-ABL1) fusion (Ph) or Ph-like ALL (USA-only) with targetable kinase-activating
lesions and either (i) or (ii) as follows: (i) For non-US sites: participants who have
relapsed or are resistant or intolerant to at least one prior therapy that contained a
BCR-ABL-targeted tyrosine kinase inhibitor (TKI); or for US sites: participants who
have relapsed or are resistant or intolerant to at least one prior therapy that
contained a second-generation BCR-ABL1-targeted TKI (ie, dasatinib, nilotinib, and
bosutinib); or (ii) have a T315I mutation. Note: A participant will be defined as
intolerant if they had a Grade ≥3 nonhematologic toxicity or a Grade 4 hematologic
toxicity considered at least possibly related to the last TKI and lasting for >2
weeks, and led to discontinuation of therapy. Eligible participants include:
1. Participants in relapse (post 0 or 1 hematopoietic stem cell transplantation
(HSCT)).
2. Participants with BCR-ABL1 T315I mutation, irrespective of relapse,
resistance/intolerance, or transplant status and irrespective of any prior TKI
use.
3. Participants with Ph-like ALL (US only) with TKI-targetable lesions involving any
of the following kinase genes: ABL1, ABL2, cerebrospinal fluid (CSF1R), and
platelet-derived growth factor receptor, beta polypeptide (PDGFRB).
4. Participants with bone marrow relapse defined as: M2 marrow (5%-24% lymphoblasts)
by morphology with confirmatory testing consisting of ≥5% lymphoblasts by flow
cytometry or BCR-ABL1 fluorescence in situ hybridization (FISH) or ≥10^-2
leukemic clone identified by immunoglobulin heavy chain-T-cell receptor
polymerase chain reaction (PCR) or M3 marrow (≥25% lymphoblasts) by morphology.
5. Participants with combined bone marrow and extramedullary disease.
2. Performance Status: Karnofsky performance status ≥50% for patients >16 years of age or
Lansky Play Scale ≥50% for patients ≤16 years of age.
3. Have recovered to less than Grade 2 National Cancer Institute common terminology
criteria for adverse events (NCI CTCAE) version 5, or to baseline, from any
nonhematologic toxicities (except alopecia) due to previous therapy.
4. Participants must meet the following criteria related to prior therapies:
- Cytoreduction with hydroxyurea: Hydroxyurea can be initiated and continued for up to
24 hours before the start of protocol therapy.
- Participants who relapsed while receiving cytotoxic therapy: At least 14 days
must have passed since the completion of the last dose of chemotherapy before the
first dose of ponatinib can be given except for the following: intrathecal (IT)
chemotherapy and/or maintenance therapy such as vincristine, mercaptopurine,
methotrexate, or glucocorticoids. There is no waiting period for those relapsing
on maintenance-like therapy.
- HSCT: Participants who have experienced relapse after a HSCT are eligible,
provided they have no evidence of acute or chronic graft-versus-host disease
(GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days
posttransplant at the time of enrollment.
- Hematopoietic growth factors: Before the first dose of ponatinib, at least 7 days
must have passed since completion of therapy with granulocyte colony-stimulating
factor or other growth factors, and at least 14 days must have passed since
completion of therapy with pegfilgrastim.
- Biologics and Targeted Therapies: Before the first dose of ponatinib, at least 7
days must have passed since the last dose of a biologic agent. For agents that
have known AEs occurring beyond 7 days after administration, this period must be
extended beyond the time during which AEs are known to occur. The duration of
this interval must be discussed with the sponsor's medical monitor/designee.
- Monoclonal antibodies: After the last dose of monoclonal antibody, at least 3
half-lives of the administered antibody must have passed before the first dose of
ponatinib.
- Immunotherapy: Before the first dose of ponatinib, at least 30 days must have
passed after the completion of any type of immunotherapy (eg, tumor vaccines,
chimeric antigen receptor T-cell [CAR-T-cell]).
- Immunosuppressive therapy: Before the first dose of ponatinib, at least 14 days
must have passed after the completion of immunosuppressive therapy (including
regimens following stem cell transplant).
- Radiotherapy: No washout period is necessary for radiation given to any
extramedullary site other than central nervous system (CNS); ≥90 days must have
passed if participant received prior total body irradiation or craniospinal or
cranial radiotherapy.
- Anthracyclines: Participants must have had a lifetime exposure of <400 mg/m^2 of
doxorubicin equivalents of anthracyclines.
5. Adequate renal, hepatic, cardiac function with normal QT function, and with no
evidence of pancreatitis.
Exclusion Criteria:
1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell leukemia.
2. A history or current diagnosis of chronic myeloid leukemia (CML).
3. Isolated extramedullary disease.
4. Diagnosis of ALL, MPAL, or Ph-like ALL (US only) with targetable kinase-activating
lesions after treatment with cytotoxic therapy for another cancer.
5. Diagnosis of another concurrent primary malignancy.
6. Clinically significant cardiovascular disease, including but not limited to:
1. Any history of myocardial infarction (MI) or unstable angina.
2. History of or presence of heart block, and/or clinically significant ventricular
or atrial arrhythmias.
3. 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.
7. 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 participants can safely discontinue the drug(s).
8. Uncontrolled hypertriglyceridemia (triglycerides ≥450 mg/dL). (Participants with
triglycerides ≥ 450 mg/dL may be enrolled in the absence of any significant
cardiovascular risk after discussion with the sponsor's medical monitor/designee.).
9. 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.
11. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or
immunotherapy while participant is on study treatment.
13. Known gastrointestinal disease or gastrointestinal procedure that could interfere with
the oral absorption of ponatinib.
14. Participants with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome.
15. Participants with Down syndrome. 16. Ongoing or active systemic infection, including
but not limited to known seropositive HIV, or known active hepatitis B or C infection.
17. Participants 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. Participants with a history of cerebrovascular ischemia/hemorrhage with residual
deficits are not eligible. (Participants with a history of cerebrovascular
ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved).
18. Uncontrolled seizure disorder. (Participants 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 vascular events.
