A Study of Ponatinib With Chemotherapy in Children, Teenagers, and Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
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|ClinicalTrials.gov Identifier: NCT04501614|
Recruitment Status : Active, not recruiting
First Posted : August 6, 2020
Last Update Posted : November 28, 2022
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This study is about an anticancer drug called ponatinib which is a tyrasine 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, a minitablet form of the ponatinib 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.
|Condition or disease||Intervention/treatment||Phase|
|Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL) Ph+ Mixed Phenotype Acute Leukemia (MPAL) Philadelphia Chromosome-Like ALL (Ph-like ALL)||Drug: Ponatinib Drug: Ponatinib AAF Drug: Chemotherapy Agents||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||68 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official 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|
|Actual Study Start Date :||February 24, 2021|
|Estimated Primary Completion Date :||February 27, 2025|
|Estimated Study Completion Date :||August 27, 2027|
Ponatinib tablet or age appropriate formulation (AAF) 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 at RP2D determined in Phase 1.
Drug: Ponatinib AAF
Ponatinib age appropriate formulation (AAF).
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.
- Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy [ Time Frame: Up to Week 4 ]The RP2D is the maximum tolerated dose (MTD) or less.
- Phase 2: Complete Remission (CR) Rate at the end of Reinduction Block [ Time Frame: Up to Week 4 ]CR rate is defined as percentage of participants with CR at end of reinduction block. CR is defined as no circulating blasts and <5% blasts in the bone marrow (BM); normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000/μl (or >100 × 10^9 platelets /L).
- Phase 1: CR Rate at the end of Reinduction Block [ Time Frame: Up to Week 4 ]CR rate is defined as percentage of participants with CR at end of reinduction block. CR is defined as no circulating blasts and <5% blasts in the BM; normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000/μl (or >100 × 10^9 platelets /L).
- Phase 1: Presence the Breakpoint Cluster Region- Abelson (BCR-ABL1) Domain Mutation Pre and Post Ponatinib Treatment [ Time Frame: Up to Week 8 ]
- Phase 2: Percentage of Participants with Continued CR or who Achieved CR at the End of Consolidation Block [ Time Frame: Up to Week 8 ]CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
- Phase 2: Percentage of Participants with Negative Minimal Residual Disease (MRD) [ Time Frame: Up to Weeks 4 and 8 ]MRD negative rate is the percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate at <0.01% threshold.
- Phase 2: Percentage of Participants who Relapsed or Progressed Following Reinduction and Consolidation [ Time Frame: Up to Weeks 4 and 8 ]
- Phase 2: Event-free Survival (EFS) [ Time Frame: Up to approximately 36 months ]EFS is defined as time from date of enrollment until death due to any cause; refractory to treatment (defined as failure to achieve CR by end of the consolidation block) or relapse from CR. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
- Phase 2: Progression-free Survival (PFS) [ Time Frame: Up to approximately 36 months ]PFS is defined as time from date of enrolment until death due to any cause; disease progression (clinical deterioration associated with disease process, including evidence of increasing blasts in the bone marrow and/or evidence of new organ involvement) or relapse from CR. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
- Phase 2: Overall Survival (OS) [ Time Frame: Up to approximately 36 months ]OS is defined as time from first dose of ponatinib until death due to any cause.
- Phase 2: Duration of Response (DOR) [ Time Frame: Up to approximately 36 months ]DOR is defined as the interval between the first assessment at which the criteria for CR are met until the time at which relapse from CR occurs. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
- Phase 2: Percentage of Participants who Underwent Hematopoietic Stem Cell Transplantation (HSCT) [ Time Frame: Up to approximately 36 months ]
- Phase 2: Presence of BCR-ABL Domain Mutation Pre and Post Ponatinib Treatment [ Time Frame: Up to Week 8 ]
- Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib [ Time Frame: Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22 ]
- Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib [ Time Frame: Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22 ]
- Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib [ Time Frame: Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22 ]
- 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) [ Time Frame: From the first dose of study drug up to 30 days after last dose of study drug (Up to 36 months) ]
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|Ages Eligible for Study:||1 Year to 21 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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.
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).
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04501614
|Study Director:||Study Director Clinical Science||Takeda|
|Other Study ID Numbers:||
2019-002549-39 ( EudraCT Number )
U1111-1225-0394 ( Other Identifier: WHO )
|First Posted:||August 6, 2020 Key Record Dates|
|Last Update Posted:||November 28, 2022|
|Last Verified:||November 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||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.|
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
|Access Criteria:||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.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Immune System Diseases
Protein Kinase Inhibitors
Molecular Mechanisms of Pharmacological Action