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

NCT04501614 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: Ponatinib-15012019-002549-39U1111-1225-0394
• Study Type: interventional
• Target: 11
• Locations: 15 countries
• Sites: 64

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.

Conditions

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

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (2)

• Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy

  The RP2D is the maximum tolerated dose (MTD) or less.

  Up to Day 35 in Phase 1

• Phase 2: Percentage of Participants With Complete Remission (CR) at the End of the Reinduction Block

  CR was defined as no circulating blasts and less than (\<)5 percent (%) blasts in the bone marrow (BM); normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) greater than (\>)1000 cells/microliter (μL) (or \>1.0 × 10\^9 cells/liter \[L\]); Platelets \>100,000/μL (or \>100 × 10\^9 platelets/L).

  Up to Day 35 in Phase 2

Secondary Outcomes (14)

• Phase 1: Number of Participants With CR at the End of Reinduction Block

  Day 35 in Phase 1

• Phase 2: Percentage of Ph+ ALL Participants Who Achieved CR at the End of Consolidation Block

  Day 70 in Phase 2

• Phase 2: Percentage of Ph+ ALL Participants With Negative Minimal Residual Disease (MRD) Among Those Who Achieved CR

  Up to Day 70 (end of consolidation block) in Phase 2

• Phase 2: Percentage of Participants Who Relapsed or Progressed Following Reinduction and Consolidation

  Up to 3 years of follow-up in Phase 2

• Phase 2: Event-free Survival (EFS)

  Up to 3 years of follow-up in Phase 2

Study Arms (1)

Ponatinib

EXPERIMENTAL

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.

Drug: Ponatinib; Drug: Chemotherapy Agents

Interventions

Ponatinib DRUG

Ponatinib tablets.

Ponatinib

Chemotherapy Agents 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.

Ponatinib

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• Weight: Participants must be weighing at least 5 kg at the time of 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 5.0, 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.

You may not qualify if:

• 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 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 milligrams per deciliter (mg/dL)).
• 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.
• 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 deoxyribonucleic acid (DNA) fragility syndromes, such as Fanconi anemia and Bloom syndrome.

Sponsors & Collaborators

• Takeda: lead

Study Sites (64)

Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Rady Childrens Hospital San Diego - PIN

San Diego, California, 92123, United States

Location

UCSF Medical Comprehensive Cancer

San Francisco, California, 94143-3010, United States

Location

Alfred I Dupont Hospital For Children

Wilmington, Delaware, 19803, United States

Location

Ann and Robert H Lurie Childrens Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Riley Hospital For Children

Indianapolis, Indiana, 46202-5128, United States

Location

Children's Mercy Hospital and Clinica

Kansas City, Missouri, 64108, United States

Location

Cincinnati Children's Hospital Medical Center - PIN

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Childrens Medical Center Research Institute at UT Southwestern

Dallas, Texas, 75235-9063, United States

Location

Hospital Universitario Austral

Pilar, Buenos Aires, B1629AHJ, Argentina

Location

Hospital Italiano de Buenos Aires

Buenos Aires, C1199ABB, Argentina

Location

Queensland Childrens Hospital

South Brisbane, Queensland, 4101, Australia

Location

Royal Children's Hospital Melbourne - PIN

Parkville, Victoria, 3052, Australia

Location

Perth Childrens Hospital

Nedlands, Western Australia, 6009, Australia

Location

Rua Ramiro Barcelos, 2350

Curitiba, Paraná, 81520-060, Brazil

Location

Irmandade Da Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Rio Grande Du Sul, 90020-090, Brazil

Location

Hospital de Clinicas de Porto Alegre (HCPA) - PPDS

Porto Alegre, Rio Grande Du Sul, 90035-903, Brazil

Location

Fundacao Pio XII Hospital de Cancer de Barretos

Barretos, São Paulo, 14784-400, Brazil

Location

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

Ribeirão Preto, 14051-140, Brazil

Location

Graacc Grupo de Apoio Ao Adolescente E A Crianca Com Cancer

São Paulo, 04039-001, Brazil

Location

Hospital Santa Marcelina

São Paulo, 08270-070, Brazil

Location

West China Second University Hospital, Sichuan Univesity

Chengdu, 610041, China

Location

Children's Hospital of Chongqing Medical University

Chongqing, 400014, China

Location

The Affiliated Hospital of Guizhou Medical University

Guiyang, 550004, China

Location

The Second Hospital of Anhui Medical University

Hefei, 230601, China

Location

Qilu Hospital of Shandong University

Jinan, 250012, China

Location

Children's Hospital of Shanghai

Shanghai, 200040, China

Location

Shanghai Childrens Medical Center

Shanghai, 200127, China

Location

Children's Hospital of Soochow University

Suzhou, 215025, China

Location

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

Tianjin, 300020, China

Location

Union Hospital Tongji Medical College Huazhong University of Science and Technology

Wuhan, 430022, China

Location

Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

Wuhan, 430030, China

Location

Fakultni nemocnice Brno

Brno, 61300, Czechia

Location

Fakultni nemocnice v Motole

Prague, 15006, Czechia

Location

Hopital Sud

Rennes, Ille-et-Vilaine, 35200, France

Location

Assistance Publique Hopitaux de Marseille

Marseille, 13385, France

Location

Hopital Robert Debre

Paris, 75019, France

Location

Hopital Des Enfants

Toulouse, 31059, France

Location

IRCCS Ospedale Pediatrico Bambino Gesu - INCIPIT - PIN

Rome, Lazio, 165, Italy

Location

Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN

Genoa, Liguria, 16147, Italy

Location

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

Monza, Lombardy, 20900, Italy

Location

Ospedale Infantile Regina Margherita - INCIPIT - PIN

Turin, Piedmont, 10126, Italy

Location

Hospital Universitario Dr. Jose Eleuterio Gonzalez

Monterrey, Nuevo León, 64460, Mexico

Location

Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca

Guadalajara, 44340, Mexico

Location

Instituto Nacional de Pediatria

Mexico City, 4530, Mexico

Location

Princess Maxima Center for Pediatric Oncology - PIN

Utrecht, 3584 CS, Netherlands

Location

Uniwersytecki Szpital Dzieciecy

Krakow, 30-663, Poland

Location

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

Zabrze, 41-800, Poland

Location

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

Lisbon, Lisbon District, 1099-023, Portugal

Location

Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS

Porto, 4200-072, Portugal

Location

Seoul National University Hospital

Seoul, 3080, South Korea

Location

Severance Hospital Yonsei University Health System

Seoul, 3722, South Korea

Location

Asan Medical Center - PPDS

Seoul, 5505, South Korea

Location

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

Seoul, 6591, South Korea

Location

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, 8035, Spain

Location

Hospital Infantil Universitario Nino Jesus - PIN

Madrid, 28009, Spain

Location

Hospital Universitario Virgen del Rocio - PPDS

Seville, 41013, Spain

Location

Royal Marsden Hospital - Surrey

Surrey Quays, Sutton, SM2 5PT, United Kingdom

Location

Cambridge University Hospitals NHS Foundation Trust

Cambridge, CB2 0QQ, United Kingdom

Location

Royal Hospital for Children (Glasgow) - PPDS - PIN

Glasgow, G3 8SJ, United Kingdom

Location

Related Links

• Related Info

MeSH Terms

Interventions

ponatinib

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2020
• First Posted: August 6, 2020
• Study Start: February 24, 2021
• Primary Completion: December 19, 2023
• Study Completion: July 19, 2024
• Last Updated: October 2, 2025
• Results First Posted: January 15, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (4); AU (3); BR (7); CN (11); US (13); ME (3); PL (2); ES (3); GB (3); CZ (2); AR (2); IT (4); NL (1); PT (2); KR (4)