Overview

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

Status:
Not yet recruiting
Trial end date:
2030-12-01
Target enrollment:
0
Participant gender:
All
Summary
This is an open-label, phase I-II dose-escalation and expansion study designed to define the recommended dose of brigatinib as monotherapy in pediatric and young adult patients with ALK+ ALCL, IMT or other solid tumors and to evaluate the pharmacokinetics (PK), (long-term) safety, and efficacy of brigatinib in these children.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Princess Maxima Center for Pediatric Oncology
Collaborator:
Takeda
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: 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.

2. Patients must have a confirmed diagnosis of cancer histologically 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:

o no response to ALCL99/other standard of care chemotherapy (SD or PD of
measurable lesions), and/or

o MRD-positivity by qualitative PCR for NPM-ALK prophase after one block
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
unresectable ALK+ IMT, or when surgery would imply severe mutilation 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:

- no response to ALCL99/other standard of care chemotherapy (SD or PD of
measurable lesions), and/or

- MRD-positivity by qualitative PCR for NPM-ALK prophase after one block
ALCL99/other standard of care chemotherapy (before the second course of
chemotherapy).

- Patients with R/R IMT Relapsed/refractory ALK+ IMT, or newly diagnosed, including
advanced and metastatic, ALK+ 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.

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 must have recovered to Grade <2 NCI CTCAE v5.0 or to baseline, from any
nonhematologic toxicities (except alopecia and peripheral neuropathy) due to
previous therapy.

- 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:

o Immunotherapy: 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.).

o Other: before the first dose of brigatinib, at least 7 days must have passed
since the last dose of a biologic agent. 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.

o Immunosuppressive therapy: Before the first dose of brigatinib, at least 14
days 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 (up
to 5 days).

o Radiotherapy (XRT): No washout period is necessary for radiation given to any
extramedullary site other than the CNS and lungs; ≥45 days must have passed if
patient received prior total body irradiation or craniospinal or cranial XRT; ≥28
days must have passed if patient received radiotherapy to the lung. For patients
receiving XRT to both lungs, or in case of stereotactic radiotherapy, the PIs
should be consulted before inclusion.

9. Patients must meet the organ function and system function requirements as stated
below:

- Patients must have adequate renal and hepatic function as indicated by the
following 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 x
institutional ULN, the patient must have a radioisotope GFR ≥ 70mL/min/1.73m2

- Adequate liver function defined as: direct bilirubin ≤1.5 times the upper
limit of normal (ULN) for age AND AST and ALT must be ≤5 times the ULN for
age (unless related to involvement of the liver or histiocytic/macrophage
inflammatory process).

- No clinical, radiological or laboratory evidence of pancreatitis, including o
Serum 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 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 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 the
patient has no signs of active bleeding or hemolysis).

10. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram OR
left ventricular ejection fraction of ≥50% by multigated acquisition scan.

11. Normal QT interval corrected per Fridericia method (QTcF) on screening
electrocardiogram (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 serum
pregnancy test confirmed prior to enrollment.

14. Female patients with infants must agree not to breastfeed their infants while on this
study.

15. Contraception:

• Male and female patients of child-bearing potential must agree to use, an effective
method for male and highly effective method for female, of contraception approved by
the investigator during the study, following the CTFG recommendations, for at least 8
months for females and for at least 5 months for males after the last dose of
brigatinib.

• Highly effective methods of contraception include (but not exclusively) the
following contraceptive methods:

o combined (estrogen- and progestogen-containing) hormonal contraception associated
with inhibition of ovulation

- progestogen-only hormonal contraception associated with inhibition of ovulation

- intrauterine device (IUD), intrauterine hormone-releasing system (IUS), sexual
abstinence.

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 the
study:

1. Patients receiving systemic treatment with strong or moderate CYP3A inhibitors or
inducers within 14 days or five half-life times 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 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 have resolved).

9. 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).