relapsed/refractory ALK rearranged** or ALK mutated tumors, including relapsed/refractory ALK+ALCL and ALK+IMT.
Conditions
Interventions
Trade Name: ALUNBRIG
Product Name: Brigatinib
Product Code: AP26113
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Brigatinib
CAS Number: 1197953-54-0
Current Sponsor code: AP26113
Othe
Sponsors
Princess Maxima Center for Pediatric Oncology in The Netherlands
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Patients must be =1 and < 26 years of age at the time of enrollment, and able to swallow brigatinib tablets at the time of enrollment, with a minimum weight of 10 kg. Note 1:for phase 1 only patients < 18 years old will be eligible. A liquid formulation for children with a weight lower than 10 kg or for those that cannot swallow tablets is in development. Note 2:for the Netherlands only a minimum age of = 5 years is required. Note 3:for the Chech Republic only, minimum age is = 4 years. 2.Patients must have a histologically confirmed diagnosis of cancer at baseline. In patients where a repeat biopsy at relapse (or moment of refractory disease) is considered not feasible by the treating physician, archived material from diagnosis needs to be available for central review. 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. For ALK+ ALCL, detection of ALK with immunohistochemistry (IHC) is sufficient for inclusion, all others require molecular evidence of a ALK fusion gene or mutation by FISH, PCR or NGS. ALK detection will be confirmed centrally with FISH. 4.For Phase 1: •Patients with ALCL must be relapsed/refractory or intolerant to standard therapies. Refractory disease for ALCL is defined as: no response to at least one course of ALCL99/other standard of care chemotherapy (SD or PD of measurable lesions), and/or MRD-positivity by qualitative PCR for NPM-ALK prophase after at least one course of ALCL99/other standard of care chemotherapy (before the second course of chemotherapy). •Patients with relapsed/refractory (R/R) IMT must not be suitable for curative surgical resection without causing mutilation. Newly diagnosed patients with locally advanced IMT, for whom surgery may not be feasible for close proximity to vital structures, without prior tumor-shrinkage, may also be included, as well as metastatic disease. •Patients with other solid tumors (excluding IMT) must have relapsed or refractory disease. 5.For Phase 2, patients must have measurable and/or evaluable disease: •Patients with ALCL must be relapsed/refractory or intolerant to standard therapies. Refractory disease for ALCL is defined as:no response to at least one course of ALCL99/other standard of care chemotherapy (SD or PD of measurable lesions), and/or MRD-positivity by qualitative PCR for NPM-ALK prophase after at least one course of ALCL99/other standard of care chemotherapy (before the second course of chemotherapy). •Patients with 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 <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. Rest see protocol Are the trial subjects under 18? yes Number of subjects for this age range: 50 F.1.2 Adults (18-64 years) y
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). 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 |
|---|---|
| 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: See protocol Phase 2: Safety (in both cohorts) •To assess the safety and tolerability of brigatinib administered as monotherapy in pediatric and AYA patients •To assess the cumulative toxicities in patients receiving multiple courses of brigatinib, including endocrine and ophthalmologic toxicities. •To describe long term toxicity (toxicity during the off-therapy period up to 5 years after study inclusion) with special attention to ocular, pulmonary, endocrine adverse events and height, weight or growth abnormalities. •To assess the acceptability and palatability of brigatinib. •To collect plasma concentration-time data for brigatinib and constructa population PK model, and to relate exposure to safety parameters. •To describe the cumulative incidence of non-relapse mortality. •To assess brigatinib related toxicity after the start of new anticancer therapy. Efficacy/activity see protocol ;Primary end point(s): Phase 1: • Dose-limiting toxicities (DLTs) during the first course of therapy. • Brigatinib plasma PK parameters to be determin | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1: see protocol Phase 2: Safety (in both cohorts) • 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. • Brigatinib plasma PK parameters 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). • Occurrence of any long-term toxicity during the off-therapy period up to 5 years after study inclusion) with special attention pulmonary, ocular, 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 In Cohort B1, ALK+ IMT: •Time to best response, defined as the time between achieving the best response and the start of treatment with brigatinib. •Duration of response (DOR), defined as the time between achieving response (CR or PR according to RECIST 1.1) after starting study treatment and documented relapse or death. •The number of IMT patients that undergo a (curative) resection after treatment with brigatinib. •Cumulative incidence of non-response or relapse and/or non-relapse mortality or pa | — |
Countries
Austria, Belgium, Czechia, Czech Republic, 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