ALK+ ALCL, IMT en andere ALK+ tumoren ALK positive tumors
Conditions
Interventions
Brigatinib will be administered orally in 28-day cycles continuously at the
assigned dose level in Phase 1 and the RP2D in Phase 2 and dosed based on body
weight. Brigatinib may be taken with or wit
Sponsors
Prinses Máxima Centrum voor Kinderoncologie
Eligibility
Age
No minimum to 64 Years
Inclusion criteria
Inclusion criteria: 1. Patients must be >=1 and = 5 years. Note 3: for the Czech Republic only, minimum age is >= 4 years. 2. Patients must have a histologically confirmed diagnosis of cancer at baseline 3. Patients are required to provide prior results showing an activating ALK aberration in the tumor per local laboratory results, and material needs to be available for central laboratory confirmation of ALK status 4. For Phase 1: • Patients with ALCL must be relapsed/refractory or intolerant to standard therapies. Refractory disease for ALCL is defined as: o no response to at least one course of ALCL99/other standard of care chemotherapy (SD or PD ), and/or o MRD-positivity by qualitative PCR for NPM-ALK after at least one course ALCL99/other standard of care chemotherapy (before the second course of chemotherapy). • Patients with relapsed/refractory (R/R) or newly diagnosed IMT must not be suitable for curative surgical resection without causing severe mutilation or risk associated with organ involvement, or have metastatic disease. • Patients with other solid tumors (excluding IMT) must have relapsed or refractory disease . • Only patients >=1 and = 5 years 5. For Phase 2, patients must have measurable and/or evaluable disease: • Patients with ALCL must be relapsed/refractory as defined. o No response to at least one course of ALCL99/other standard of care chemotherapy (SD or PD), and/or o MRD-positivity by qualitative PCR for NPM-ALK after at least one course of ALCL99/other standard of care chemotherapy (before the second course of chemotherapy). • Patients with R/R IMT Relapsed/refractory IMT, or newly diagnosed, including locally advanced and metastatic IMT which cannot be surgically resected without causing mutilation. 6. Performance Status: • Karnofsky performance status >=40% for patients >=16 years of age or Lansky Play Scale >=40% for patients =50% for patients >=16 years of age or Lansky Play Scale >=50% for patients =0.75 × 10 9/L, except in case of macrophage activation syndrome (MAS) or bone marrow involvement. • Platelet count o In phase 1: Platelet count: >=75 × 10^9/ L, except in case of MAS or bone marrow involvement o In phase 2: : Platelet count: >=75 × 10^9/ L, except in case of MAS or bone marrow involvement. For patients
Exclusion criteria
Exclusion criteria: 1. Patients receiving systemic treatment with strong or moderate CYP3A inhibitors or inducers within 14 days or five half-lives, whichever the less, prior to the first dose of study drug (refer to Section 5.2 for a list of example medications). 2. Diagnosis of another concurrent primary malignancy. 3. Clinically significant cardiovascular disease, including any of the following: • Myocardial infarction or unstable angina within 6 months of study entry. • 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. 4. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or immunotherapy while patient is on study treatment. 5. Any illness that affects gastrointestinal absorption. 6. Ongoing or active systemic infection, active seropositive HIV, or known active hepatitis B or C infection. 7. Any pre-existing 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 brigatinib. 8. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. 9. 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 have resolved). 10. 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). 11. Patients with electrolytes imbalances >= grade 2 NCI CTCAE v5.0 are not eligible (supplementation or medical intervention is allowed to correct electrolyte imbalance before inclusion). 12. Patients with uncontrolled diabetes, i.e. patients with persistent hyperglycemia >= grade 2 NCI CTCAE v5.0 despite well conducted treatment with either oral anti glycemic agent and/or insulin are not eligible (patients with well controlled diabetes with either insulin or oral anti glycemic agents are eligible).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1: • Dose-limiting toxicities (DLTs) during the first course of therapy. • Brigatinib plasma PK parameters to be determined: o maximum observed concentration (Cmax), o time of first occurrence of maximum observed concentration (Tmax), o area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast). • The RP2D will be selected by the DSMB and will be based on the dose that results in equivalent (approximately ±20% of the adult values) PK exposure to the adult comparator and with | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase 1: Safety • Adverse events (AEs), as characterized by type, frequency, severity (graded using CTCAE v5.0), including ocular, pulmonary, endocrine AEs, and height, weight or growth abnormalities, timing and relation to the study therapy, during the first and subsequent courses of therapy. • Occurrence of toxic death, i.e. death attributable to brigatinib therapy, as well as other causes of death. • Laboratory abnormalities as characterized by type, frequency, severity and timing. • The cumulative incidence of non-relapse mortality, with time calculated between start of study treatment and death. • Palatability questionnaire during two years of treatment (for frequency see SOE table). • Acceptability: diary reporting number of times a dose was not effectively administered. • Occurrence of any long-term toxicity during the off-therapy period up to 5 years after study inclusion with special attention to ocular, pulmonary, endocrine AEs, and height, weight or growth abnormalities . • Collection of grade 3 or higher AEs and AESIs, suspected by the investigator to be related to brigatinib after the start of new anticancer therapy. Activity/efficacy • ORR, defined as CR or PR, by RECIST 1.1 for solid tumors (other than neuroblastoma or brain tumors), by IPNHL (International Pediatric revised Response Criteria for Malignant Lymphoma) for ALCL, by NANT (New Approaches to Neuroblastoma Therapy) response criteria for neuroblastoma, by RANO (Responses Assessment in Neuro-Oncology) criteria for brain tumors, measured after 1 course and as best response during brigatinib treatment, • Time to best response, defined as the time between achieving the best response and the start of treatment with brigatinib For patients with ALCL; qualitative minimal residual disease (MRD) measured at multiple timepoints during treatment, including the percentage of patients who become MRD-negative, and time to MRD negativation. • Cumulative incidence of non-resp | — |
Countries
Netherlands
Outcome results
None listed