Brentuximab vedotin+Adriamycin, vinblastine, and dacarbazine in pediatric patients with advanced stage newly diagnosed Hodgkin lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Jul 2017 → ongoing

Decision date (initial)

2024-01-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2023-506415-18-00

EudraCT number

2015-004112-38

WHO UTN

U1111-1171-0984

ClinicalTrials.gov

NCT02979522

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Dose response

Phase 1 Primary Objective:
 To assess the safety and tolerability, and to identify the recommended dose of brentuximab vedotin when combined with multiagent chemotherapy regimen AVD for first-line treatment of advanced stage HL in pediatric patients.

Phase 2 Primary Objectives:
 To evaluate the CR rate of pediatric patients with advanced stage HL at the end of protocol therapy.
 To determine the percentage of patients who are PET- after 2 cycles of protocol therapy.
 To evaluate the PR rate of pediatric patients with advanced stage HL at the end of protocol therapy.
 To evaluate the ORR of pediatric patients with advanced stage HL at the end of protocol therapy.
 To determine the percentage of patients who are able to complete 6 cycles of protocol therapy at the recommended dose.

Secondary objectives 2

1. Phase 1 Secondary Objectives:  To describe the maximum observed concentration (Cmax), area under the concentration-time curve from time 0 to 15 days (AUC0-15), and time of first time of occurrence of Cmax (Tmax) of brentuximab vedotin, monomethyl auristatin E (MMAE), and total (free and conjugated) therapeutic antibody (TAb). For further - please refer to Protocol
2. Phase 2 Secondary Objectives:  To evaluate the progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and duration of response (DOR) in pediatric patients with advanced stage HL treated with protocol therapy. For further - please refer to Protocol

Conditions and MedDRA coding

Hodgkin lymphoma (HL) - Hodgkin lymphoma (HL), a neoplasm of lymphoid tissue which is histopathologically defined by the presence of malignant Hodgkin Reed-Sternberg (HRS) cells in a background of inflammatory cells. The proposed pediatric study has been designed to evaluate brentuximab vedotin as a component of a multiagent frontline chemotherapy regimen in patients with advanced stage, newly diagnosed HL, here defined as Stage III and Stage IV and a ≥50 Lansky Play-Performance or Karnofsky Performance Status.

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000980-PIP01-10

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Main Criteria for Inclusion: Male or female patients aged 5 to <18 years with newly diagnosed classical CD30+ advanced stage (Stage III and Stage IV) HL who are treatment naïve with Karnofsky Performance Status or Lansky Play- Performance ≥50.

Exclusion criteria 1

1. Main Criteria for Exclusion: Patients may not have nodular lymphocyte-predominant HL, known active cerebral meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML, sensory or motor peripheral neuropathy, or known hypersensitivity to brentuximab vedotin or any component of AVD.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Phase 1: Determination of the recommended dose of brentuximab vedotin in combination with AVD in a pediatric population.
2. Phase 1: Percentage of patients who experience AEs from the first dose of protocol therapy through 30 days after administration of the last dose of protocol therapy.
3. Phase 1: Percentage of patients who experience serious AEs (SAEs) from the first dose of protocol therapy through 30 days after administration of the last dose of protocol therapy.
4. Phase 2: Percentage of patients who achieve a CR per IRF assessment at EOT per IWG criteria.
5. Phase 2: Percentage of patients whose disease is PET- after 2 cycles of protocol therapy per IRF assessment.
6. Phase 2: Percentage of patients who achieve a PR per IRF assessment at EOT per IWG criteria.
7. Phase 2: Percentage of patients who achieve an OR per IRF assessment at EOT per IWG criteria.
8. Phase 2: Percentage of patients who are able to complete 6 cycles of protocol therapy at the recommended dose.

Secondary endpoints 20

1. Phase 1: Mean Cmax and mean AUC0-15 of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma).
2. Phase 1: Median Tmax of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma).
3. Phase 1: Percentage of patients who achieve a CR per independent review facility (IRF) assessment at End of Treatment (EOT) per International Working Group (IWG) criteria.
4. Phase 1: Percentage of patients who achieve a PR per IRF assessment at EOT per IWG criteria.
5. Phase 1: Percentage of patients who achieve an overall response (OR) per IRF assessment at EOT per IWG criteria.
6. Phase 1: Percentage of patients whose disease is PET- after 2 cycles of protocol therapy per IRF assessment.
7. Phase 1: Percentage of patients whose disease is PET+ after 6 cycles of protocol therapy per IRF assessment.
8. Phase 1: Percentage of patients who are ATA positive, persistently positive, or transiently positive, ATA titer and neutralizing ATA (nATA) positive at baseline, predose Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, or at termination if treatment is terminated before Cycle 6, and at EOT
9. Phase 1: Impact of ATA and nATA on the safety, efficacy, and PK endpoints.
10. Phase 2: PFS, EFS, OS, DOR.
11. Phase 2: Percentage of patients receiving irradiation for HL following study treatment.
12. Phase 2: Percentage of patients who experience AEs from the first dose of protocol therapy through 30 days after administration of the last dose of protocol therapy.
13. Phase 2: Percentage of patients who experience SAEs from the first dose of protocol therapy through 30 days after administration of the last dose of protocol therapy.
14. Phase 2: Percentage of patients who are ATA positive, persistently positive, or transiently positive, ATA titer and nATA positive at baseline, predose Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, or at termination if treatment is terminated before Cycle 6, and at EOT.
15. Phase 2: Impact of ATA and nATA on the safety, efficacy, and PK endpoints.
16. Phase 2: Mean Cmax and mean AUC0-15 of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma).
17. Phase 2: Median Tmax of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma).
18. Phase 2: Percentage of patients who experience peripheral neuropathy, regardless of seriousness, from the first dose of protocol therapy through study closure.
19. Phase 2: Time to onset and time to resolution for all peripheral neuropathy events.
20. Phase 2: Immune reconstitution (peripheral blood CD34+ count; enumeration of the total lymphocyte count and lymphocyte subsets; total Ig and IgG, IgM, and IgA levels; and levels of the antibodies to tetanus, HiB, and polio serotypes) at baseline, EOT, and at 6, 12, and 18 months (±1 month) after last dose, until the start of subsequent anticancer therapy (with the exception of radiotherapy administered as part of first-line therapy).

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

95 Hayden Avenue

City

Lexington

Postcode

02421-7942

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Bipin Savani

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda Development Center Americas Inc.

Third parties 6

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 28 files

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

Application history

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