A Study of Ponatinib With Chemotherapy in Children, Teenagers, and Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL), Ph+ Mixed Phenotype Acute Leukemia (MPAL), Philadelphia Chromosome-Like ALL (Ph-like ALL)
About this trial
This is an interventional treatment trial for Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL) focused on measuring Drug Therapy
Eligibility Criteria
Inclusion Criteria:
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.
- Performance Status: Karnofsky performance status ≥50% for participants >16 years of age or Lansky Play Scale ≥50% for participants ≤16 years of age.
- 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.
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.
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.
No clinical, radiological or laboratory evidence of pancreatitis, including:
- Serum lipase must be <2 times the ULN, and
- Serum amylase must be <2 times the ULN.
- 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:
- A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell leukemia.
- A history or current diagnosis of chronic myeloid leukemia (CML).
- Diagnosis of ALL, MPAL, or Ph-like ALL (US only) with targetable kinase-activating lesions after treatment with cytotoxic therapy for another cancer.
- Diagnosis of another concurrent primary malignancy.
Clinically significant cardiovascular disease, including but not limited to:
- Any history of myocardial infarction (MI) or unstable angina.
- History of or presence of heart block, and/or clinically significant ventricular or atrial arrhythmias.
- 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.
- 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).
- Uncontrolled hypertriglyceridemia (triglycerides ≥450 mg/dL).
- 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.
- Previous treatment with ponatinib.
- Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or immunotherapy while participant is on study treatment.
- Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption of ponatinib.
- Participants with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome.
- Participants with Down syndrome.
- Participants with uncontrolled systemic infection, or known laboratory and/or clinical evidence of active infection with HIV, hepatitis B, or hepatitis C.
- 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 and causative factor(s) have resolved).
- 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).
- History of severe coagulopathy or cardiovascular or peripheral vascular events.
- Treatment with live attenuated vaccinations within 30 days prior to initiation of study treatment regimen.
Sites / Locations
- Phoenix Childrens HospitalRecruiting
- Arkansas Children's HospitalRecruiting
- Children's Hospital Los AngelesRecruiting
- Rady Childrens Hospital San Diego - PINRecruiting
- UCSF Medical Comprehensive CancerRecruiting
- Alfred I Dupont Hospital For ChildrenRecruiting
- Ann and Robert H Lurie Childrens Hospital of ChicagoRecruiting
- Riley Hospital For ChildrenRecruiting
- Dana Farber Cancer Institute
- Children's Mercy Hospital and ClinicaRecruiting
- Cincinnati Children's Hospital Medical Center - PINRecruiting
- Nationwide Children's HospitalRecruiting
- Children's Hospital of PhiladelphiaRecruiting
- St Jude Children's Research HospitalRecruiting
- Childrens Medical Center Research Institute at UT SouthwesternRecruiting
- Hospital Universitario AustralRecruiting
- Hospital Italiano de Buenos AiresRecruiting
- Queensland Childrens HospitalRecruiting
- Royal Children's Hospital Melbourne - PINRecruiting
- Perth Childrens HospitalRecruiting
- Rua Ramiro Barcelos, 2350Recruiting
- Irmandade Da Santa Casa de Misericordia de Porto AlegreRecruiting
- Hospital de Clinicas de Porto Alegre (HCPA) - PPDSRecruiting
- Clinica SUPRA
- Fundacao Pio XII Hospital de Cancer de BarretosRecruiting
- Hospital Das Clinicas da Faculdade de Medicina de Ribeirao Preto - USPRecruiting
- Graacc Grupo de Apoio Ao Adolescente E A Crianca Com CancerRecruiting
- Hospital Santa MarcelinaRecruiting
- West China Second University Hospital, Sichuan UnivesityRecruiting
- Children's Hospital of Chongqing Medical UniversityRecruiting
- The Affiliated Hospital of Guizhou Medical UniversityRecruiting
- The Second Hospital of Anhui Medical UniversityRecruiting
- Qilu Hospital of Shandong University
- The Affiliated Hospital of Qingdao University
- Children's Hospital of ShanghaiRecruiting
- Shanghai Childrens Medical CenterRecruiting
- Children's Hospital of Soochow UniversityRecruiting
- Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical SciencesRecruiting
- Union Hospital Tongji Medical College Huazhong University of Science and TechnologyRecruiting
- Tongji Hospital Tongji Medical College Huazhong University of Science and TechnologyRecruiting
- Fakultni nemocnice BrnoRecruiting
- Fakultni nemocnice v MotoleRecruiting
- Hopital SudRecruiting
- Assistance Publique Hopitaux de MarseilleRecruiting
- Hopital Robert DebreRecruiting
- Hopital Des EnfantsRecruiting
- IRCCS Ospedale Pediatrico Bambino Gesu - INCIPIT - PINRecruiting
- Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PINRecruiting
- Fndazione MBBM (MONZA E BRIANZA PER IL BAMBINO E LA SUA MAMMA) - c/o Centro Maria Letizia VergaRecruiting
- Ospedale Infantile Regina Margherita - INCIPIT - PINRecruiting
- Seoul National University HospitalRecruiting
- Severance Hospital Yonsei University Health SystemRecruiting
- Asan Medical Center - PPDSRecruiting
- The Catholic University of Korea, Seoul St. Mary's HospitalRecruiting
- Hospital Universitario Dr. Jose Eleuterio GonzalezRecruiting
- Instituto Nacional de PediatriaRecruiting
- Nuevo Hospital Civil de Guadalajara Dr. Juan I. MenchacaRecruiting
- Princess Maxima Center for Pediatric Oncology - PINRecruiting
- Uniwersytecki Szpital DzieciecyRecruiting
- SPZOZ Centralny Szpital Kliniczny UM w LodziRecruiting
- SPSK Nr 1 im. Prof.Stanislawa Szyszko Slaskiego Uniwersytetu MedycznegoRecruiting
- Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E.Recruiting
- Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDSRecruiting
- Hospital Universitario Vall d'Hebron - PPDSRecruiting
- Hospital Infantil Universitario Nino Jesus - PINRecruiting
- Hospital Universitario Virgen del Rocio - PPDSRecruiting
- Royal Marsden Hospital - SurreyRecruiting
- Birmingham Childrens Hospital
- Cambridge University Hospitals NHS Foundation TrustRecruiting
- Royal Hospital for Children (Glasgow) - PPDS - PINRecruiting
Arms of the Study
Arm 1
Experimental
Ponatinib
Ponatinib tablet or age appropriate formulation (AAF) [i.e., capsules with ponatinib minitablets], based on age and weight, in combination with chemotherapy backbone, orally, once daily in both reinduction block and consolidation block (35 days each including 29 days of treatment followed by rest period from chemotherapy for a minimum of 6 days consisting of daily ponatinib only) in Phase 1 to determine RP2D. In Phase 2 participants will receive ponatinib at RP2D in combination with chemotherapy backbone.