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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04501614




Registration number
NCT04501614
Ethics application status
Date submitted
4/08/2020
Date registered
6/08/2020

Titles & IDs
Public title
A Study of Ponatinib With Chemotherapy in Children, Teenagers, and Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Scientific title
A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation
Secondary ID [1] 0 0
2019-002549-39
Secondary ID [2] 0 0
Ponatinib-1501
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL) 0 0
Ph+ Mixed Phenotype Acute Leukemia (MPAL) 0 0
Philadelphia Chromosome-Like ALL (Ph-like ALL) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ponatinib
Treatment: Drugs - Ponatinib AAF
Treatment: Drugs - Chemotherapy Agents

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.


Treatment: Drugs: Ponatinib
Ponatinib tablets.

Treatment: Drugs: Ponatinib AAF
Ponatinib age appropriate formulation i.e., capsules with ponatinib minitablets.

Treatment: Drugs: 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 code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy
Timepoint [1] 0 0
Up to Week 4
Primary outcome [2] 0 0
Phase 2: Complete Remission (CR) Rate at the end of Reinduction Block
Timepoint [2] 0 0
Up to Week 4
Secondary outcome [1] 0 0
Phase 1: CR Rate at the end of Reinduction Block
Timepoint [1] 0 0
Up to Week 4
Secondary outcome [2] 0 0
Phase 2: Percentage of Ph+ ALL Participants or who Achieved CR at the End of Consolidation Block
Timepoint [2] 0 0
Up to Week 8
Secondary outcome [3] 0 0
Phase 2: Percentage of Ph+ ALL Participants with Negative Minimal Residual Disease (MRD) Among Those who Achieved CR
Timepoint [3] 0 0
Up to Weeks 4 and 8
Secondary outcome [4] 0 0
Phase 2: Percentage of Participants who Relapsed or Progressed Following Reinduction and Consolidation
Timepoint [4] 0 0
Up to Weeks 4 and 8
Secondary outcome [5] 0 0
Phase 2: Event-free Survival (EFS)
Timepoint [5] 0 0
Up to approximately 36 months
Secondary outcome [6] 0 0
Phase 2: Progression-free Survival (PFS)
Timepoint [6] 0 0
Up to approximately 36 months
Secondary outcome [7] 0 0
Phase 2: Overall Survival (OS)
Timepoint [7] 0 0
Up to approximately 36 months
Secondary outcome [8] 0 0
Phase 2: Duration of Response (DOR)
Timepoint [8] 0 0
Up to approximately 36 months
Secondary outcome [9] 0 0
Phase 2: Percentage of Participants who Underwent Hematopoietic Stem Cell Transplantation (HSCT)
Timepoint [9] 0 0
Up to approximately 36 months
Secondary outcome [10] 0 0
Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib
Timepoint [10] 0 0
Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22
Secondary outcome [11] 0 0
Phase 1: tmax: Time of First Occurrence of Cmax for Ponatinib
Timepoint [11] 0 0
Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22
Secondary outcome [12] 0 0
Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib
Timepoint [12] 0 0
Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22
Secondary outcome [13] 0 0
Phase 1 and 2: Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs)
Timepoint [13] 0 0
From the first dose of study drug up to 30 days after last dose of study drug (Up to 36 months)

Eligibility
Key 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).
Minimum age
1 Year
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
NA
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
24/02/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
19/07/2024
Sample size
Target
Accrual to date
Final
11
Recruitment in Australia
Recruitment state(s)
QLD,VIC,WA
Recruitment hospital [1] 0 0
Queensland Childrens Hospital - South Brisbane
Recruitment hospital [2] 0 0
Royal Children's Hospital Melbourne - PIN - Parkville
Recruitment hospital [3] 0 0
Perth Childrens Hospital - Nedlands
Recruitment postcode(s) [1] 0 0
4101 - South Brisbane
Recruitment postcode(s) [2] 0 0
3052 - Parkville
Recruitment postcode(s) [3] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arkansas
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Delaware
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Indiana
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
Ohio
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
Tennessee
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas
Country [11] 0 0
Argentina
State/province [11] 0 0
Buenos Aires
Country [12] 0 0
Brazil
State/province [12] 0 0
Parana
Country [13] 0 0
Brazil
State/province [13] 0 0
Rio Grande Du Sul
Country [14] 0 0
Brazil
State/province [14] 0 0
Sao Paulo
Country [15] 0 0
Brazil
State/province [15] 0 0
Ribeirao Preto
Country [16] 0 0
China
State/province [16] 0 0
Chengdu
Country [17] 0 0
China
State/province [17] 0 0
Chongqing
Country [18] 0 0
China
State/province [18] 0 0
Guiyang
Country [19] 0 0
China
State/province [19] 0 0
Hefei
Country [20] 0 0
China
State/province [20] 0 0
Jinan
Country [21] 0 0
China
State/province [21] 0 0
Shanghai
Country [22] 0 0
China
State/province [22] 0 0
Suzhou
Country [23] 0 0
China
State/province [23] 0 0
Tianjin
Country [24] 0 0
China
State/province [24] 0 0
Wuhan
Country [25] 0 0
Czechia
State/province [25] 0 0
Brno
Country [26] 0 0
Czechia
State/province [26] 0 0
Praha
Country [27] 0 0
France
State/province [27] 0 0
Ille-et-Vilaine
Country [28] 0 0
France
State/province [28] 0 0
Marseille
Country [29] 0 0
France
State/province [29] 0 0
Paris
Country [30] 0 0
France
State/province [30] 0 0
Toulouse
Country [31] 0 0
Italy
State/province [31] 0 0
Lazio
Country [32] 0 0
Italy
State/province [32] 0 0
Liguria
Country [33] 0 0
Italy
State/province [33] 0 0
Lombardia
Country [34] 0 0
Italy
State/province [34] 0 0
Piemonte
Country [35] 0 0
Korea, Republic of
State/province [35] 0 0
Seoul
Country [36] 0 0
Mexico
State/province [36] 0 0
Nuevo Leon
Country [37] 0 0
Mexico
State/province [37] 0 0
Ciudad De Mexico
Country [38] 0 0
Mexico
State/province [38] 0 0
Guadalajara
Country [39] 0 0
Netherlands
State/province [39] 0 0
Utrecht
Country [40] 0 0
Poland
State/province [40] 0 0
Krakow
Country [41] 0 0
Poland
State/province [41] 0 0
Zabrze
Country [42] 0 0
Portugal
State/province [42] 0 0
Lisboa
Country [43] 0 0
Portugal
State/province [43] 0 0
Porto
Country [44] 0 0
Spain
State/province [44] 0 0
Barcelona
Country [45] 0 0
Spain
State/province [45] 0 0
Madrid
Country [46] 0 0
Spain
State/province [46] 0 0
Sevilla
Country [47] 0 0
United Kingdom
State/province [47] 0 0
Sutton
Country [48] 0 0
United Kingdom
State/province [48] 0 0
Cambridge
Country [49] 0 0
United Kingdom
State/province [49] 0 0
Glasgow

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Takeda
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Study Director
Address 0 0
Takeda
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR)
When will data be available (start and end dates)?
Available to whom?
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://vivli.org/ourmember/takeda/


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04501614