A Study of Ponatinib With Chemotherapy in Children, Teenagers, and Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

NCT ID: NCT04501614

Last Updated: 2025-10-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 11 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-24
• Study Completion Date: 2024-07-19

Brief Summary

This study is about an anticancer drug called ponatinib which is a tyrosine kinase inhibitor given with chemotherapy to children, teenagers, and young adults up to 21 years of age with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia who have relapsed or are resistant to other treatment.

The main aims of this study are to confirm the highest dose of ponatinib tablets and minitablet capsules that can be given to participants with acceptable side effects, and to evaluate if participant's leukemia achieves remission.

Participants will take ponatinib tablets with chemotherapy. For participants who cannot swallow tablets or who are receiving less than a 10 milligrams (mg) dose, a capsule with small ponatinib minitablets inside will be provided. Participants will take ponatinib for 10 weeks in combination with chemotherapy (reinduction and consolidation blocks) and will be followed up for at least 3 years.

Detailed Description

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 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 or who are receiving less than a 10 mg dose will receive the age-appropriate formulation, capsule with ponatinib minitablets inside:

• 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.

Conditions

Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL); Ph+ Mixed Phenotype Acute Leukemia (MPAL); Philadelphia Chromosome-Like ALL (Ph-like ALL)

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ponatinib

Ponatinib tablets, based on 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.

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

Chemotherapy Agents

Intervention Type: DRUG

Chemotherapy agents for reinduction include vincristine, dexamethasone, polyethylene glycol (PEG)-asparaginase (Erwinia asparaginase when PEG-asparaginase is not available), daunorubicin. Agents for intrathecal (IT) chemotherapy, central nervous system (CNS)-1/2: IT methotrexate chemotherapy, or CNS-3: triple intrathecal (ITT) methotrexate, hydrocortisone, cytarabine. Chemotherapy agents for consolidation include dexamethasone, vincristine, methotrexate, PEG-asparaginase (Erwinia asparaginase when PEG-asparaginase is not available), cyclophosphamide, etoposide, CNS-1/2: IT methotrexate chemotherapy, CNS-3: ITT chemotherapy methotrexate, hydrocortisone, cytarabine. The doses for chemotherapy agents for reinduction will be given as per standard of care.

Interventions

Ponatinib

Ponatinib tablets.

Intervention Type: DRUG

Chemotherapy Agents

Chemotherapy agents for reinduction include vincristine, dexamethasone, polyethylene glycol (PEG)-asparaginase (Erwinia asparaginase when PEG-asparaginase is not available), daunorubicin. Agents for intrathecal (IT) chemotherapy, central nervous system (CNS)-1/2: IT methotrexate chemotherapy, or CNS-3: triple intrathecal (ITT) methotrexate, hydrocortisone, cytarabine. Chemotherapy agents for consolidation include dexamethasone, vincristine, methotrexate, PEG-asparaginase (Erwinia asparaginase when PEG-asparaginase is not available), cyclophosphamide, etoposide, CNS-1/2: IT methotrexate chemotherapy, CNS-3: ITT chemotherapy methotrexate, hydrocortisone, cytarabine. The doses for chemotherapy agents for reinduction will be given as per standard of care.

Intervention Type: DRUG

Eligibility Criteria

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 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 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 ribonucleic acid (RNA) sequencing or by alternative accredited method used by the site.

c) Disease status: (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); OR (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 related to the last TKI and lasting for >2 weeks, and led to discontinuation of therapy.

2. Weight: Participants must be weighing at least 5 kg at the time of enrollment.

3. Performance Status: Karnofsky performance status ≥50% for participants ≥16 years of age or Lansky Play Scale ≥50% for participants <16 years of age.

4. Have recovered to less than Grade 2 National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) Version 5.0, or to baseline, from any nonhematologic toxicities (except alopecia) due to previous therapy.

5. 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 milligrams per square meter (mg/m^2) of doxorubicin equivalents of anthracyclines.

6. 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.

7. 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.

8. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) OR left ventricular ejection fraction of ≥50% by ECHO or multigated acquisition scan (MUGA).

9. Normal QT interval with Fridericia correction method (QTcF) on screening electrocardiogram (ECG), defined as QTcF of ≤450 milliseconds (ms).

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 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 milligrams per deciliter (mg/dL)).

8. Current systemic use of any medications or herbal supplements that are known to be strong inhibitors or strong inducers of cytochrome P450 3A (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 deoxyribonucleic acid (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 human immunodeficiency virus (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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

Rady Childrens Hospital San Diego - PIN

San Diego, California, United States

UCSF Medical Comprehensive Cancer

San Francisco, California, United States

Alfred I Dupont Hospital For Children

Wilmington, Delaware, United States

Ann and Robert H Lurie Childrens Hospital of Chicago

Chicago, Illinois, United States

Riley Hospital For Children

Indianapolis, Indiana, United States

Children's Mercy Hospital and Clinica

Kansas City, Missouri, United States

Cincinnati Children's Hospital Medical Center - PIN

Cincinnati, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

St Jude Children's Research Hospital

Memphis, Tennessee, United States

Childrens Medical Center Research Institute at UT Southwestern

Dallas, Texas, United States

Hospital Universitario Austral

Pilar, Buenos Aires, Argentina

Hospital Italiano de Buenos Aires

Buenos Aires, , Argentina

Queensland Childrens Hospital

South Brisbane, Queensland, Australia

Royal Children's Hospital Melbourne - PIN

Parkville, Victoria, Australia

Perth Childrens Hospital

Nedlands, Western Australia, Australia

Rua Ramiro Barcelos, 2350

Curitiba, Paraná, Brazil

Irmandade Da Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Rio Grande Du Sul, Brazil

Hospital de Clinicas de Porto Alegre (HCPA) - PPDS

Porto Alegre, Rio Grande Du Sul, Brazil

Fundacao Pio XII Hospital de Cancer de Barretos

Barretos, São Paulo, Brazil

Hospital Das Clinicas da Faculdade de Medicina de Ribeirao Preto - USP

Ribeirão Preto, , Brazil

Graacc Grupo de Apoio Ao Adolescente E A Crianca Com Cancer

São Paulo, , Brazil

Hospital Santa Marcelina

São Paulo, , Brazil

West China Second University Hospital, Sichuan Univesity

Chengdu, , China

Children's Hospital of Chongqing Medical University

Chongqing, , China

The Affiliated Hospital of Guizhou Medical University

Guiyang, , China

The Second Hospital of Anhui Medical University

Hefei, , China

Qilu Hospital of Shandong University

Jinan, , China

Children's Hospital of Shanghai

Shanghai, , China

Shanghai Childrens Medical Center

Shanghai, , China

Children's Hospital of Soochow University

Suzhou, , China

Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences

Tianjin, , China

Union Hospital Tongji Medical College Huazhong University of Science and Technology

Wuhan, , China

Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

Wuhan, , China

Fakultni nemocnice Brno

Brno, , Czechia

Fakultni nemocnice v Motole

Prague, , Czechia

Hopital Sud

Rennes, Ille-et-Vilaine, France

Assistance Publique Hopitaux de Marseille

Marseille, , France

Hopital Robert Debre

Paris, , France

Hopital Des Enfants

Toulouse, , France

IRCCS Ospedale Pediatrico Bambino Gesu - INCIPIT - PIN

Rome, Lazio, Italy

Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN

Genoa, Liguria, Italy

Fndazione MBBM (MONZA E BRIANZA PER IL BAMBINO E LA SUA MAMMA) - c/o Centro Maria Letizia Verga

Monza, Lombardy, Italy

Ospedale Infantile Regina Margherita - INCIPIT - PIN

Turin, Piedmont, Italy

Hospital Universitario Dr. Jose Eleuterio Gonzalez

Monterrey, Nuevo León, Mexico

Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca

Guadalajara, , Mexico

Instituto Nacional de Pediatria

Mexico City, , Mexico

Princess Maxima Center for Pediatric Oncology - PIN

Utrecht, , Netherlands

Uniwersytecki Szpital Dzieciecy

Krakow, , Poland

SPSK Nr 1 im. Prof.Stanislawa Szyszko Slaskiego Uniwersytetu Medycznego

Zabrze, , Poland

Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E.

Lisbon, Lisbon District, Portugal

Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS

Porto, , Portugal

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital Yonsei University Health System

Seoul, , South Korea

Asan Medical Center - PPDS

Seoul, , South Korea

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, , South Korea

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, , Spain

Hospital Infantil Universitario Nino Jesus - PIN

Madrid, , Spain

Hospital Universitario Virgen del Rocio - PPDS

Seville, , Spain

Royal Marsden Hospital - Surrey

Surrey Quays, Sutton, United Kingdom

Cambridge University Hospitals NHS Foundation Trust

Cambridge, , United Kingdom

Royal Hospital for Children (Glasgow) - PPDS - PIN

Glasgow, , United Kingdom

Countries

United States; Argentina; Australia; Brazil; China; Czechia; France; Italy; Mexico; Netherlands; Poland; Portugal; South Korea; Spain; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.takeda.com/study-detail/5f929169296beb001e63bf5d

Related Info

Other Identifiers

2019-002549-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1225-0394

Identifier Type: OTHER

Identifier Source: secondary_id

Ponatinib-1501

Identifier Type: -

Identifier Source: org_study_id