Brigatinib in pediatric and young adult patients with ALK+ ALCL, IMT or other solid tumors (Briga-PED)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prinses Maxima Centrum voor Kinderoncologie B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 May 2022 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda

External identifiers

EU CT number

2024-513412-10-00

EudraCT number

2021-002713-34

ClinicalTrials.gov

NCT04925609

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety, Pharmacodynamic, Pharmacokinetic

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.
To establish the anti-tumor activity of single agent brigatinib when administered to children with ALK+ IMT.
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 objectives 7

1. To assess the safety and tolerability of brigatinib administered as monotherapy in pediatric and AYA patients during course 1, as well as the cumulative toxicities in patients receiving multiple courses of brigatinib.
2. To assess the acceptability and palatability of brigatinib.
3. 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
4. Cohort B1: To estimate the activity of brigatinib in terms of: o time to best response, o duration of response (DOR), o the number of patients that undergo a complete (microscopic radical R0) resection after treatment with brigatinib, o cumulative incidence of non-response or relapse on treatment and during follow-up, o event-free survival (EFS), o overall survival (OS), o on treatment survival.
5. Cohort B2: To estimate the activity of brigatinib in terms of: o ORR after one course and best ORR during brigatinib treatment, o time to best response, o duration of response (DOR), o the cumulative incidence of non-response or relapse on treatment and after two years of brigatinib treatment, o overall survival (OS), o on treatment survival, o To describe outcome for ALCL patients with and without HSCT, after a remission induced with brigatinib. o To describe anti-tumor activity for ALCL patients that are re-challenged with brigatinib for a relapse occurring after brigatinib discontinuation.
6. Cohort B2R: To estimate the activity of brigatinib re-treatment in terms of: o ORR after one course and best ORR during brigatinib re-treatment, o time to best response, o duration of response (DOR), o the cumulative incidence of non-response or relapse on treatment and after 24 cycles of brigatinib re-treatment, o overall survival (OS), o on treatment survival,
7. Cohort B1R: To estimate the activity of brigatinib re-treatment in terms of: o time to best response, o duration of response (DOR), o the number of patients that undergo a complete (microscopic radical R0) resection after treatment with brigatinib, o cumulative incidence of non-response or relapse on treatment and during follow-up, o event-free survival (EFS), o overall survival (OS), o on treatment survival.

Conditions and MedDRA coding

Anaplastic Large Cell Lymphoma (ALCL)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002296-PIP01-17

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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.
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. 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 at least one course of ALCL99/other standard of care chemotherapy (SD or PD of measurable lesions), and/or o MRD-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. Phase 2: • Patients with ALCL must be relapsed/refractory. Refractory disease for ALCL is defined as: o no response to at least one course of ALCL99/other standard of care chemotherapy (SD or PD of measurable lesions), and/or o MRD-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. Cohort B1R and B2R: Patients who were previously treated in the phase 1 or phase 2 part of this study, who completed brigatinib treatment as defined in this protocol, who responded to prior brigatinib treatment on protocol, and who developed a relapse or progression within 12 months after completion of brigatinib treatment (defined as per the EOT visit date).

Exclusion criteria 2

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Phase 1: dose-limiting toxicities (DLTs) during the first course of therapy.
2. Phase 1: 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).
3. Phase 1: 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.
4. Cohort B1: 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.
5. Cohort B2: 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.
6. Cohort B1R: 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 re-treatment.
7. Cohort B2R: EFS (using the IPNHL response criteria), defined as the time between restart 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prinses Maxima Centrum voor Kinderoncologie B.V.

Sponsor organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Michel Zwaan

Public contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Secretary TDC

Third parties 1

Locations

12 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 178 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications