Acute lymphoblastic leukemia leukemia
Conditions
Interventions
Patients are treated with ponatinib for 70 days. In addition to ponatinib,
patients receive chemotherapy. Although no standard protocol is available for
these patients, the chemotherapy used will be
Sponsors
Takeda Development Center Americas, Inc.
Eligibility
Age
No minimum to 64 Years
Inclusion criteria
Inclusion criteria: Phase 1 cohort 1 (enrollment and treatment completed) eligibility criteria at the time of enrollment for patients to be administered ponatinib as the tablet formation: - Patients must have a body weight >=30 kg. - Patients must be able to swallow solid oral dosage forms. Phase 1 cohort 2 eligibility criteria at the time of enrollment: - Patients must be aged >=1 year and have a body weight of at least 5 kg. Each patient must meet all the following inclusion criteria to be enrolled in the study for phase 1 and phase 2. 1. Diagnosis: Patients must have a diagnosis of Ph+ ALL, 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. Patients 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 RNA sequencing or by alternative accredited method used by the site. Referring institution*s laboratory results will be accepted for diagnosis and study enrollment. No confirmation by a sponsor central laboratory is required. c. Disease status: i. For non-US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at least 1 prior therapy that contained a BCR-ABL1-targeted TKI, OR For US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at least 1 prior therapy that contained a second-generation BCR-ABL1-targeted TKI (ie, 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. Referring institution*s laboratory results will be accepted for enrollment; however, the mutation needs to be confirmed by the central laboratory. If the mutational status is not concordant, the patient will be withdrawn from the study and excluded from analyses for RP2D and efficacy, but included for safety. A patient 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. Age: Patients must be >=1 and =50% for patients >16 years of age or Lansky Play Scale >=50% for patients <=16 years of age. 4. Patients must have recovered to less than Grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events version 5, or to baseline, from any nonhematologic toxicities (except alopecia) due to previous t
Exclusion criteria
Exclusion criteria: 1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell leukemia. 2. A history or current diagnosis of CML. 3. Diagnosis of ALL, MPAL, or Ph-like ALL (US only) 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: a. Any history of myocardial infarction (MI) or unstable angina. b. History of or presence of heart block, and/or clinically significant ventricular or atrial arrhythmias. c. 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 patient can safely discontinue the drug(s). 7. Uncontrolled hypertriglyceridemia (triglycerides >=450 mg/dL). (Patients 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) 8. 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. 9. Previous treatment with ponatinib. 10. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or immunotherapy while patient is on study treatment. 11. Known allergy or contraindications to any of the drugs (active or excipient) used in the study. 12. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption of ponatinib. 13. Patients with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome. 14. Patients with Down syndrome. 15. Patients with uncontrolled systemic infection, or know laboratory an/or clinical evidence of active infection with HIV, hepatitis B, or hepatitis C. 16. Patients 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. 17. Patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible. (Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits and causative factor(s) have resolved.) 18. Uncontrolled seizure disorder. (Patients 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 cardiovascular or peripheral vascular events. 20. Any condition or illness that, in the opinion of the investigator or sponsor, would compromise patient safety or interfere with the evaluation of the safety or efficacy of ponatinib. 21. Admission or evidence of illicit use, drug abuse, or alcohol abuse. 22. Pregn
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1 Primary Endpoint * * RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. Phase 2 Primary Endpoint * * CR at the end of the reinduction block. CR is defined as 1000/µL, and platelet count of >100,000/µL. | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase 1 Secondary Endpoints * * CR at the end of the reinduction block. CR is defined as 1000/µL, and platelet count of >100,000/µL. Phase 2 Secondary Endpoints * * Ph+ ALL only: Proportion of patients who achieved CR at the end of consolidation * Ph+ ALL only: Proportion of patients with MRD-negative status ( | — |
Countries
Netherlands
Outcome results
None listed