not applicable

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Nationwide Childrens Hospital

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Oct 2024 → ongoing

Decision date (initial)

2024-05-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-508953-16-00

ClinicalTrials.gov

NCT04655404

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

• To assess the disease control rate (Complete Response [CR], Continued Complete Response [CCR], Partial Response [PR] and Stable Disease [SD]) of larotrectinib in young children with newly diagnosed HGG with NTRK fusion after 2 cycles of larotrectinib monotherapy
• To assess the feasibility and safety of larotrectinib when given in combination with chemotherapy in young children with newly diagnosed HGG with NTRK fusion, and the safety of larotrectinib when given post-focal radiation therapy

Secondary objectives 2

1. To assess the objective response rate (ORR) (CR and PR) of larotrectinib in children with newly diagnosed HGG with NTRK fusion after 2 cycles of larotrectinib monotherapy
2. To assess overall (OS) and progression-free survivals (PFS) of children with HGG treated with a larotrectinib-containing regimen at 1, 3 and 5 years and compared to historical data from BABYPOG and HIT-SKK

Conditions and MedDRA coding

Newly diagnosed high grade glioma (HGG) including diffuse intrinsic pontine glioma (DIPG)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Age: Patients ≤ 21 years of age (birth to 21 years of age excluding preterm newborn infants) at the time of study enrollment will be eligible.
2. Diagnosis: Patients with newly-diagnosed HGG, including DIPG, whose tumors are documented in a CLIA/CAP certified lab (or clinically equivalent method considered standard in non-US sites) to harbor an NTRK fusion alteration by FISH, PCR, or next generation sequencing are eligible. Patients must have had histologically verified HGG such as anaplastic astrocytoma, glioblastoma, or H3 K27-mutant diffuse midline glioma verified at a CONNECT site.
3. Disease status: Patients with disseminated DIPG or HGG are eligible only if the patient is to receive chemotherapy only, i.e. no craniospinal RT is intended to be given. MRI of spine must be performed if disseminated disease is suspected clinically by the treating physicians. Patients with primary spinal tumors are eligible only if the patient is to receive either chemotherapy or focal radiation therapy, i.e. no craniospinal RT is intended to be given. Patients with leptomeningeal disease only, with no definitive identifiable primary tumor, and documented NTRK fusion, must be discussed with the Study Chair on a case-by-case basis.
4. Performance level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
5. Prior therapy:  Patients must not have received any prior anti-cancer chemotherapy,  Prior use of corticosteroids is allowed
6. Organ function requirement: Adequat bone marrow function defined as:  Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3,  Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment),  Hemoglobin >8 g/dL (may receive transfusions)
7. Organ function requirement: Adequate renal function defined as:  Serum creatinine within normal institutional limits, OR  Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2
8. Organ function requirement: Adequate liver function defined as:  Total bilirubin ≤ 2.5 × institutional upper limit of normal,  AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal
9. Organ function requirement: Adequate pulmonary function defined as:  Pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest)
10. Organ function requirement: Adequate neurologic function defined as:  Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
11. Informed consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion criteria 10

1. Pregnancy or breast-feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
2. Concomitant medications: Investigational Drugs: Patients who have previously received or are currently receiving another investigational drug are not eligible. Anti-cancer Agents: Patients who have previously received or are currently receiving other anti-cancer agents, including chemotherapy, immunotherapy, monoclonal antibodies, biologic or targeted therapy, are not eligible.
3. Infection: Patients must not have any active, uncontrolled systemic bacterial, viral or fungal infection.
4. Patients who have received prior solid organ transplantation are not eligible.
5. Patients must not have malabsorption syndrome or other condition affecting oral absorption.
6. Patients must not be receiving any treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer. Strong inducers or inhibitors of CYP3A4 should be avoided from 7 days prior to enrollment to the end of the study.
7. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
8. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
9. Patient is dependent on the Sponsor, Investigator or trial site
10. Minors who will not be capable of giving consent when they reach the legal age of majority

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Disease control rate (CR, CCR, PR, SD) presented as frequency and percentage. Time frame: At the end of cycle 2
2. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. Time frame: From Day 1 of Course 1 of combination treatment with chemotherapy/ from Day 1 of treatment after radiotherapy through 30 days following end of protocol treatment

Investigational products

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

Test 3

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Nationwide Childrens Hospital

Sponsor organisation

Nationwide Childrens Hospital

Address

700 Childrens Drive Suite W2011

City

Columbus

Postcode

43205-2664

Country

United States

Scientific contact point

Organisation

Nationwide Childrens Hospital

Contact name

KiTZ Clinical Trial Group

Public contact point

Organisation

Nationwide Childrens Hospital

Contact name

KiTZ Clinical Trial Group

Third parties 2

Locations

1 EU/EEA country · 5 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 15 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