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JOURNAL ONKOLOGIE – STUDIE

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

Noch nicht rekrutierend

NCT-Nummer:
NCT04501614

Studienbeginn:
März 2021

Letztes Update:
24.12.2020

Wirkstoff:
Ponatinib, Ponatinib AAF, Chemotherapy Agents

Indikation (Clinical Trials):
Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphoid, Philadelphia Chromosome

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Takeda

Collaborator:
-

Studienleiter

Medical Director Clinical Science
Study Director
Takeda

Kontakt

Studienlocations (3 von 51)

Universitatsklinikum Giesen und Marburg GmbH
35392 Giesen
(Hessen)
Germany» Google-Maps
Ansprechpartner:
Site Contact
Phone: 4964198543421
E-Mail: christine.mauz-koerholz@paediat.med.uni-giessen.de» Ansprechpartner anzeigen
Childrens Medical Center Research Institute at UT Southwestern
75235-9063 Dallas
United States» Google-Maps
Ansprechpartner:
Site Contact
Phone: 214-456-7000
E-Mail: tamra.slone@utsouthwestern.edu» Ansprechpartner anzeigen
Hospital Das Clinicas da Faculdade de Medicina de Ribeirao Preto - USP
14051-140 Ribeirao Preto
Brazil» Google-Maps
Ansprechpartner:
Site Contact
Phone: 551639636482
E-Mail: mbergamo@hcrp.usp.br» Ansprechpartner anzeigen
Fndazione MBBM (MONZA E BRIANZA PER IL BAMBINO E LA SUA MAMMA) - c/o Centro Maria Letizia Verga
20900 Monza
Italy» Google-Maps
Ansprechpartner:
Site Contact
Phone: 390392334915
E-Mail: verix.leo@gnail.com» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. 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.

2. 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. 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).

Secondary outcome:

1. 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. 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).

2. Phase 1: Presence of Breakpoint Cluster Region- Abelson (BCR-ABL1) Domain Mutation Pre and Post Ponatinib Treatment (Time Frame - Up to Week 8)

3. 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).

4. 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.

5. Phase 2: Percentage of Participants who Relapsed or Progressed Following Reinduction and Consolidation (Time Frame - Up to Weeks 4 and 8)

6. 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 (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).

7. 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).

8. 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.

9. 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).

10. Phase 2: Percentage of Participants who Underwent Hematopoietic Stem Cell Transplantation (HSCT) (Time Frame - Up to approximately 36 months)

11. Phase 2: Presence of BCR-ABL Domain Mutation Pre and Post Ponatinib Treatment (Time Frame - Up to Week 8)

12. 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)

13. 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)

14. 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)

15. 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))

Geprüfte Regime

  • Ponatinib:
    Ponatinib tablets.
  • Ponatinib AAF:
    Ponatinib age appropriate formulation (AAF).
  • Chemotherapy Agents:
    Chemotherapy agents for reinduction include vincristine, dexamethasone, polyethylene glycol (PEG)-asparaginase, 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, cyclophosphamide, etoposide. The doses for chemotherapy agents for reinduction will be given as per standard of care.

Quelle: ClinicalTrials.gov


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