Brigatinib in Pediatric and Young Adult Patients With ALK+ ALCL, IMT or Other Solid Tumors

Inclusion Criteria: 1. Patients must be 1 and < 26 years of age at the time of enrollment, and able toswallow brigatinib tablets at the time of enrollment, with a minimum weight of 10 kg.Note: for phase 1 only patients ≤18 years old will be eligible, A liquid formulationfor children with a weight lower than 10 kg or for those that cannot swallow tabletsis in development. 2. Patients must have a confirmed diagnosis of cancer histologically at baseline. Inpatients where a repeat biopsy at relapse (or moment of refractory disease) isconsidered not feasible by the treating physician, archived material from diagnosisneeds to be available for central review. 3. Patients are required to provide prior results showing an activating ALK aberration inthe tumor per local laboratory results, and material needs to be available for centrallaboratory confirmation of ALK status. For ALK+ ALCL, detection of ALK withimmunohistochemistry (IHC) is sufficient for inclusion, all others require molecularevidence of a ALK fusion gene or mutation by FISH, PCR or NGS. ALK detection will beconfirmed centrally with FISH. 4. For Phase 1: - Patients with ALCL must be relapsed/refractory or intolerant to standardtherapies. Refractory disease for ALCL is defined as: o no response to ALCL99/other standard of care chemotherapy (SD or PD ofmeasurable lesions), and/or o MRD-positivity by qualitative PCR for NPM-ALK prophase after one blockALCL99/other standard of care chemotherapy (before the second course ofchemotherapy). - Patients with relapsed/refractory (R/R) IMT must not be suitable for curativesurgical resection without causing mutilation. Newly diagnosed patients withunresectable ALK+ IMT, or when surgery would imply severe mutilation may also beincluded, as well as metastatic disease. - Patients with other solid tumors (excluding IMT) must have relapsed or refractorydisease. 5. For Phase 2, patients must have measurable and/or evaluable disease: - Patients with ALCL must be relapsed/refractory. Refractory disease for ALCL isdefined as: - no response to ALCL99/other standard of care chemotherapy (SD or PD ofmeasurable lesions), and/or - MRD-positivity by qualitative PCR for NPM-ALK prophase after one blockALCL99/other standard of care chemotherapy (before the second course ofchemotherapy). - Patients with R/R IMT Relapsed/refractory ALK+ IMT, or newly diagnosed, includingadvanced and metastatic, ALK+ IMT which cannot be surgically resected withoutcausing mutilation 6. Performance Status: Karnofsky performance status ≥40% for patients >16 years of age orLansky Play Scale ≥40% for patients ≤16 years of age. 7. Patients must not be receiving other investigational medications (defined as medicinalproducts 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 forbrigatinib can be included in this study. - Patients must have recovered to Grade <2 NCI CTCAE v5.0 or to baseline, from anynonhematologic toxicities (except alopecia and peripheral neuropathy) due toprevious therapy. - Patients who relapsed while receiving cytotoxic therapy: at least 14 days musthave passed since the completion of the last dose of chemotherapy before thefirst dose of brigatinib can be given. - Patients who have experienced relapse after a prior HSCT are eligible, providedthey have no evidence of acute or chronic graft-versus-host disease (GVHD), arenot receiving GVHD prophylaxis or treatment, and are at least 45 daysposttransplant at the time of enrollment. - Hematopoietic growth factors: before the first dose of brigatinib, at least 7days must have passed since completion of therapy with granulocytecolony-stimulating factor or other growth factors, and at least 14 days must havepassed since completion of therapy with pegfilgrastim. - Biologics and Targeted Therapies: o Immunotherapy: Before the first dose of brigatinib, at least 30 days must havepassed after the completion of any type of immunotherapy, (i.e. monoclonalantibodies [anti-PD1/PDL1], tumor vaccines, chimeric antigen receptor [CAR] Tcells, etc.). o Other: before the first dose of brigatinib, at least 7 days must have passedsince the last dose of a biologic agent. For agents that have known adverseevents (AEs) occurring beyond 7 days after administration, this period must beextended beyond the time during which AEs are known to occur. The duration ofthis interval must be discussed with the sponsor's medical monitor/designee. o Immunosuppressive therapy: Before the first dose of brigatinib, at least 14days must have passed after the completion of immunosuppressive therapy (including regimens following stem cell transplant). o For symptomatic patients that urgently need relief (i.e. airway obstruction),therapeutic doses of corticosteroids may be administered for a short course (upto 5 days). o Radiotherapy (XRT): No washout period is necessary for radiation given to anyextramedullary site other than the CNS and lungs; ≥45 days must have passed ifpatient received prior total body irradiation or craniospinal or cranial XRT; ≥28days must have passed if patient received radiotherapy to the lung. For patientsreceiving XRT to both lungs, or in case of stereotactic radiotherapy, the PIsshould be consulted before inclusion. 9. Patients must meet the organ function and system function requirements as statedbelow: - Patients must have adequate renal and hepatic function as indicated by thefollowing laboratory values: o Patient's serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 xinstitutional ULN, the patient must have a radioisotope GFR ≥ 70mL/min/1.73m2 - Adequate liver function defined as: direct bilirubin ≤1.5 times the upperlimit of normal (ULN) for age AND AST and ALT must be ≤5 times the ULN forage (unless related to involvement of the liver or histiocytic/macrophageinflammatory process). - No clinical, radiological or laboratory evidence of pancreatitis, including oSerum lipase must be <2 × the ULN, and o Serum amylase must be <2 × the ULN. - Absolute neutrophil count: ≥0.75 × 10 9/L, except in case of macrophageactivation syndrome (MAS) or bone marrow involvement. - Platelet count o In phase 1: Platelet count: ≥75 × 10^9/ L, except in case of MASor bone marrow involvement o In phase 2: : Platelet count: ≥75 × 10^9/ L, exceptin case of MAS or bone marrow involvement. For patients post SCT, platelet count ≥50 × 10^9/ L is accepted.Hemoglobin ≥8 g/dL or 5.0 mmol/L (red blood cell [RBC]transfusions to achieve this value are allowed with the condition that thepatient has no signs of active bleeding or hemolysis). 10. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram ORleft ventricular ejection fraction of ≥50% by multigated acquisition scan. 11. Normal QT interval corrected per Fridericia method (QTcF) on screeningelectrocardiogram (ECG), defined as QTcF of ≤450 ms. 12. Have a life expectancy of ≥3 months. 13. Female patients of childbearing potential must have a negative urine or serumpregnancy test confirmed prior to enrollment. 14. Female patients with infants must agree not to breastfeed their infants while on thisstudy. 15. Contraception: • Male and female patients of child-bearing potential must agree to use, an effectivemethod for male and highly effective method for female, of contraception approved bythe investigator during the study, following the CTFG recommendations, for at least 8months for females and for at least 5 months for males after the last dose ofbrigatinib. • Highly effective methods of contraception include (but not exclusively) thefollowing contraceptive methods: o combined (estrogen- and progestogen-containing) hormonal contraception associatedwith inhibition of ovulation - progestogen-only hormonal contraception associated with inhibition of ovulation - intrauterine device (IUD), intrauterine hormone-releasing system (IUS), sexualabstinence. 16. Voluntary written informed consent according to law and regulations

Exclusion Criteria: Patients meeting any of the following exclusion criteria are not to be enrolled in thestudy:

1. Patients receiving systemic treatment with strong or moderate CYP3A inhibitors orinducers within 14 days or five half-life times whichever the less prior to the firstdose 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 ventricularor atrial arrhythmias.
• Uncontrolled hypertension defined as persistent elevation of systolic and/ordiastolic blood pressures to ≥95th percentile based on age, sex, and heightpercentiles 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 activehepatitis B or C infection.
7. Any pre-existing condition or illness that, in the opinion of the investigator orsponsor, would compromise patient safety or interfere with the evaluation of thesafety or efficacy of brigatinib.
8. Patients with a history of cerebrovascular ischemia/hemorrhage with residual deficitsare not eligible (patients with a history of cerebrovascular ischemia/hemorrhageremain eligible provided all neurologic deficits have resolved).
9. Uncontrolled seizure disorder (patients with seizure disorders that do not requireantiepileptic drugs, or are well controlled with stable doses of antiepileptic drugsare eligible).