relapsed/refractory ALK rearranged** or ALK mutated tumors, including relapsed/refractory ALK+ALCL and ALK+IMT.
Conditions
Sponsors
Princess Maxima Center for Pediatric Oncology in The Netherlands
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Patients must be =1 and 16 years of age or Lansky Play Scale =40% for patients =16 years of age for ALCL patients in phase 2. •Karnofsky performance status =50% for patients >16 years of age or Lansky Play Scale =50% for patients =16 years of age, for IMT and other solid tumors and for ALCL patients in phase 1. 7.Patients must not be receiving other investigational medications (defined as medicinal products not yet approved for any indications, including alternative/herbal therapies) within 30 days of first dose of study drug or while on study. 8.For patients receiving prior therapy: •Patients who already received previous treatment with ALK inhibitors except for brigatinib can be included in this study. •Patients who relapsed while receiving cytotoxic therapy: at least 14 days must have passed since the completion of the la
Exclusion criteria
Exclusion criteria: Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1: • To determine the MTD/RP2D regimen of brigatinib monotherapy when administered in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors, including ALK+ IMT. • To characterize the PK of brigatinib administered as monotherapy in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors, including ALK+ IMT. Note that: o If the MTD is not reached at the highest proposed test dose, no further dose-escalation will be performed. o Pediatric PK data, compared to exposure in adults, will be taken into consideration to determine the RP2D. Phase 2: • Cohort B1, ALK+ IMT: To establish the anti-tumor activity of single agent brigatinib when administered to children with ALK+ IMT. • Cohort B2, ALK+ ALCL: To establish the efficacy of single agent brigatinib when administered to children with ALK+ ALCL for a duration of 2 years, without planned HSCT in consolidation.;Secondary Objective: Phase 1: To assess: • safety and tolerability • aAcceptability and palatability • To describe long term toxicity • To describe the anti-tumor activity and survival estimates • To assess the cumulative incidence of non-response or relapse • To describe the outcome for ALCL patients with and without SCT • To describe anti-tumor activity for ALCL patients • To describe histological response in resected specimens from IMT patients undergoing surgery • To describe on treatment survival, Phase 2: Safety (in both cohorts) • To assess the safety and tolerability • To assess the cumulative toxicities • To describe long term toxicity • To assess the acceptability and palatability of brigatinib. • To collect plasma concentration-time data for brigatinib and construct a population PK model, and to relate exposure to safety parameters. • To describe the cumulative incidence of non-relapse mortality. Efficacy/activity: see protocol.......;Primary end point(s): Phase 1: • Dose-limiting toxicities (DLTs) during the first course of therapy. • Brigatinib p | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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 . 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-response or relapse and/or non-relapse mortality or patient withdrawal due to side effects in a competing risk model. • Duration of response (DOR), defin | — |
Countries
Austria, Belgium, Czechia, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Netherlands, Norway, Poland, Spain, Sweden, Switzerland, United Kingdom
Contacts
Public ContactMaaike Boonstra-Schelfhorst
Princess Maxima Center for Pediatric Oncology in The Netherlands
Outcome results
None listed