| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsed/refractory ALK rearranged** or ALK mutated tumors, including relapsed/refractory ALK+ALCL and ALK+IMT. |
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| E.1.1.1 | Medical condition in easily understood language |
| a tumour with an ALK positive aberration |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
Phase 1: To assess:
• safety and tolerability
• acceptability and palatability of brigatinib.
• 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....... |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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:
ono response to at least one course of ALCL99/other standard of care chemotherapy (SD or PD of measurable lesions), and/or
oMRD-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 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. Refractory disease for ALCL is defined as:
ono response to at least one course of ALCL99/other standard of care chemotherapy (SD or PD of measurable lesions), and/or
oMRD-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 ≤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 last dose of chemotherapy before the first dose of brigatinib can be given.
•Patients who have experienced relapse after a prior HSCT are eligible, provided they have no evidence of acute or chronic graft-versus-host disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 45 days posttransplant at the time of enrollment.
•Hematopoietic growth factors: before the first dose of brigatinib, at least 7 days must have passed since completion of therapy with granulocyte colony-stimulating factor or other growth factors, and at least 14 days must have passed since completion of therapy with pegfilgrastim.
•Biologics and Targeted Therapies:
oImmunotherapy: before the first dose of brigatinib, at least 30 days must have passed after the completion of any type of immunotherapy, (i.e. monoclonal antibodies [anti-PD1/PDL1], tumor vaccines, chimeric antigen receptor [CAR] T cells, etc.).
oOther: before the first dose of brigatinib, at least 7 days must have passed since the last dose of a biologic agent, including any other ALK inhibitor. For agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor’s medical monitor/designee.
rest see protocol
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| E.4 | Principal 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).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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 <2 out of 6 patients at this dose level present with a DLT and taking into account responses observed in phase 1.
Phase 2:
In Cohort B1, ALK+ IMT :
• Overall response rate (ORR), defined as the percentage of patients with CR or PR according to RECIST 1.1 after 1 course and best ORR during brigatinib treatment.
In Cohort B2, ALK+ ALCL:
• EFS (using the IPNHL response criteria), defined as the time between start of study treatment and first event being progressive disease, relapse, death of any cause and second malignancies, whatever happens first. Patients consolidated with HSCT will be censored.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | 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), defined as the time between achieving response (CR or PR) after starting study treatment and documented disease progression, relapse or death.
• EFS, defined as the time between start of study treatment and first event: relapse, progressive disease, death of any cause and second malignancies, whichever happens first.
• OS, defined as time to death following start of study treatment.
• Number of patients with IMT that undergo a complete (microscopic radical R0) resection after treatment with brigatinib.
• Comparison of survival estimates for ALCL patients consolidated with SCT with patients that did not receive consolidation for SCT.
• ORR, defined as CR or PR, (by IPNHL), measured after 1 course and as best response during brigatinib treatment (re-induction) in patients with ALCL that relapse after brigatinib discontinuation and that are subsequently re-challenged with brigatinib.
• Number and percentage of IMT patients with completely necrotic tumors by pathology evaluation.
• Duration of on treatment survival, defined as time from first treatment date to disease progression, death, or discontinuation of treatment for any reason (e.g., toxicity, patient/physician preference, or initiation of a new treatment without documented progression, using RECIST 1.1 or IPNHL response criteria).
Phase 2 :
Safety (in both cohorts)
• Adverse events (AEs), as characterized by type, frequency, severity (graded using CTCAE v5.0), including pulmonary, ocular, endocrine AEs and height, weight or growth abnormalities, timing and relation to the study therapy, during brigatinib treatment.
• 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, defined as the cumulative probability 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.
Activity/efficacy: see protocol
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Israel |
| United Kingdom |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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