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). Ph+ mixed phenotype acute leukemia (Ph+ MPAL), or Philadelphia
chromosome-like ALL (US only) 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 participants. 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 6.5 years. Participants will make multiple visits to the clinic, and may be
contacted by telephone in at least 36 months of follow-up after treatment.
Inclusion Criteria:
1. Participants must have a diagnosis of Ph+ ALL, Philadelphia chromosome-positive plus
mixed phenotype acute leukemia (Ph+ MPAL), or Ph-like ALL (US only) with:
a) Involvement of 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. Participants 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 (US only) with
targetable kinase-activating lesions involving any of the following kinase genes:
ABL1, ABL2, CSF1R, and PDGFRB.
and either (i) or (ii) as follows: (i) For non-US sites: participants who have
relapsed (post 0 or 1 HSCT) 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 (post 0 or 1 HSCT) or are resistant or
intolerant to at least one prior therapy that contained a second-generation
BCR-ABL1-targeted TKI (i.e, dasatinib, nilotinib, and bosutinib) (ii) Have a BCR-ABL1
T315I mutation irrespective of relapse, resistance/intolerance, or transplant status
and irrespective of any prior TKI use.
Notes:
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.
Participants with Ph-like ALL (US only): Referring institution's laboratory results
will be accepted for study enrollment.
2. Performance Status: Karnofsky performance status ≥50% for participants >16 years of
age or Lansky Play Scale ≥50% for participants ≤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. a) Adequate renal function defined as: Estimated glomerular filtration rate (eGFR)
using the Schwartz formula, OR radioisotope glomerular filtration rate (GFR)≥70
mL/min/1.73 m^2, OR a normal serum creatinine based on age and sex.
b)Adequate liver function defined as: Direct bilirubin ≤1.5 times the upper limit of
normal (ULN) for age AND ALT ≤5 times the ULN for age.
6. No clinical, radiological or laboratory evidence of pancreatitis, including:
1. Serum lipase must be <2 times the ULN, and
2. Serum amylase must be <2 times the ULN.
7. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO)
OR left ventricular ejection fraction of ≥50% by multigated acquisition scan (MUGA).
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. 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:
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.
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 participants 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 participant is on study treatment.
11. Known gastrointestinal disease or gastrointestinal procedure that could interfere with
the oral absorption of ponatinib.
12. Participants with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome.
13. Participants with Down syndrome.
14. Participants with uncontrolled systemic infection, or known laboratory and/or clinical
evidence of active infection with HIV, hepatitis B, or hepatitis C.
15. 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.
16. 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 and causative
factor(s) have resolved).
17. 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).
18. History of severe coagulopathy or cardiovascular or peripheral vascular events.
19. Treatment with live attenuated vaccinations within 30 days prior to initiation of
study treatment regimen.
