Clinical Trials /

Ponatinib With Chemotherapy in Pediatric Participants With Relapsed, Resistant, or Intolerant Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) or Have the T315I Mutation

NCT04501614

Description:

The purpose of the study is to determine the recommended phase 2 dose (RP2D) of ponatinib (tablet and age-appropriate formulation [AAF]) in combination with chemotherapy in Phase 1 and the efficacy of ponatinib in combination with chemotherapy as measured by the rate of complete remission (CR) at the end of the reinduction block at the RP2D.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Mixed Phenotype Acute Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ponatinib With Chemotherapy in Pediatric Participants With Relapsed, Resistant, or Intolerant Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) or Have the T315I Mutation
  • 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

Clinical Trial IDs

  • ORG STUDY ID: Ponatinib-1501
  • SECONDARY ID: 2019-002549-39
  • NCT ID: NCT04501614

Conditions

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

Interventions

DrugSynonymsArms
PonatinibPonatinib
Ponatinib AAFPonatinib
Chemotherapy AgentsPonatinib

Purpose

The purpose of the study is to determine the recommended phase 2 dose (RP2D) of ponatinib (tablet and age-appropriate formulation [AAF]) in combination with chemotherapy in Phase 1 and the efficacy of ponatinib in combination with chemotherapy as measured by the rate of complete remission (CR) at the end of the reinduction block at the RP2D.

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) 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 patients. 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 36 months. Participants will make multiple visits to the clinic, and may be
      contacted by telephone in follow-up after treatment.
    

Trial Arms

NameTypeDescriptionInterventions
PonatinibExperimentalPonatinib 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.
  • Ponatinib
  • Ponatinib AAF
  • Chemotherapy Agents

Eligibility Criteria

        Inclusion Criteria:

          1. Have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotype acute
             leukemia (MPAL) with definite evidence of breakpoint cluster region- Abelson 1
             (BCR-ABL1) fusion (Ph) or Ph-like ALL (USA-only) with targetable kinase-activating
             lesions and either (i) or (ii) as follows: (i) For non-US sites: participants who have
             relapsed 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 or are resistant or intolerant to at least one prior therapy that
             contained a second-generation BCR-ABL1-targeted TKI (ie, dasatinib, nilotinib, and
             bosutinib); or (ii) have a T315I mutation. Note: 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. Eligible participants include:

               1. Participants in relapse (post 0 or 1 hematopoietic stem cell transplantation
                  (HSCT)).

               2. Participants with BCR-ABL1 T315I mutation, irrespective of relapse,
                  resistance/intolerance, or transplant status and irrespective of any prior TKI
                  use.

               3. Participants with Ph-like ALL (US only) with TKI-targetable lesions involving any
                  of the following kinase genes: ABL1, ABL2, cerebrospinal fluid (CSF1R), and
                  platelet-derived growth factor receptor, beta polypeptide (PDGFRB).

               4. Participants with bone marrow relapse defined as: M2 marrow (5%-24% lymphoblasts)
                  by morphology with confirmatory testing consisting of ≥5% lymphoblasts by flow
                  cytometry or BCR-ABL1 fluorescence in situ hybridization (FISH) or ≥10^-2
                  leukemic clone identified by immunoglobulin heavy chain-T-cell receptor
                  polymerase chain reaction (PCR) or M3 marrow (≥25% lymphoblasts) by morphology.

               5. Participants with combined bone marrow and extramedullary disease.

          2. Performance Status: Karnofsky performance status ≥50% for patients >16 years of age or
             Lansky Play Scale ≥50% for patients ≤16 years of age.

          3. 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.

          4. 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.

          5. Adequate renal, hepatic, cardiac function with normal QT function, and with no
             evidence of pancreatitis.

        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. Isolated extramedullary disease.

          4. Diagnosis of ALL, MPAL, or Ph-like ALL (US only) with targetable kinase-activating
             lesions after treatment with cytotoxic therapy for another cancer.

          5. Diagnosis of another concurrent primary malignancy.

          6. 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.

          7. 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).

          8. Uncontrolled hypertriglyceridemia (triglycerides ≥450 mg/dL). (Participants with
             triglycerides ≥ 450 mg/dL may be enrolled in the absence of any significant
             cardiovascular risk after discussion with the sponsor's medical monitor/designee.).

          9. 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.

        11. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or
        immunotherapy while participant is on study treatment.

        13. Known gastrointestinal disease or gastrointestinal procedure that could interfere with
        the oral absorption of ponatinib.

        14. Participants with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome.

        15. Participants with Down syndrome. 16. Ongoing or active systemic infection, including
        but not limited to known seropositive HIV, or known active hepatitis B or C infection.

        17. 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 have resolved).

        18. 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).

        19. History of severe coagulopathy or vascular events.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy
Time Frame:Up to Week 4
Safety Issue:
Description:The RP2D is the maximum tolerated dose (MTD) or less.

Secondary Outcome Measures

Measure:Phase 1: CR Rate at the end of Reinduction Block
Time Frame:Up to Week 4
Safety Issue:
Description:CR rate is defined as percentage of participants with 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; absolute neutrophil count (ANC) >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000/μl (or >100 × 10^9 platelets /L).
Measure:Phase 1: Presence of Breakpoint Cluster Region- Abelson (BCR-ABL1) Domain Mutation Pre and Post Ponatinib Treatment
Time Frame:Up to Week 8
Safety Issue:
Description:
Measure:Phase 2: Percentage of Participants with Continued CR or who Achieved CR at the End of Consolidation Block
Time Frame:Up to Week 8
Safety Issue:
Description: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).
Measure:Phase 2: Percentage of Participants with Negative Minimal Residual Disease (MRD)
Time Frame:Up to Weeks 4 and 8
Safety Issue:
Description:MRD negative rate is the percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate at <0.01% threshold.
Measure:Phase 2: Percentage of Participants who Relapsed or Progressed Following Reinduction and Consolidation
Time Frame:Up to Weeks 4 and 8
Safety Issue:
Description:
Measure:Phase 2: Event-free Survival (EFS)
Time Frame:Up to approximately 36 months
Safety Issue:
Description:EFS is defined as time from date of enrollment until death due to any cause; refractory to treatment (no disease response 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).
Measure:Phase 2: Progression-free Survival (PFS)
Time Frame:Up to approximately 36 months
Safety Issue:
Description: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).
Measure:Phase 2: Overall Survival (OS)
Time Frame:Up to approximately 36 months
Safety Issue:
Description:OS is defined as time from first dose of ponatinib until death due to any cause.
Measure:Phase 2: Duration of Response (DOR)
Time Frame:Up to approximately 36 months
Safety Issue:
Description: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).
Measure:Phase 2: Percentage of Participants who Underwent Hematopoietic Stem Cell Transplantation (HSCT)
Time Frame:Up to approximately 36 months
Safety Issue:
Description:
Measure:Phase 2: Presence of BCR-ABL Domain Mutation Pre and Post Ponatinib Treatment
Time Frame:Up to Week 8
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Phase 1 and 2: Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), 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)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Takeda

Trial Keywords

  • Drug Therapy

Last Updated

August 4, 2020