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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04655404


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT04655404
Ethics application status
Date submitted
9/11/2020
Date registered
7/12/2020
Date last updated
13/05/2024

Titles & IDs
Public title
A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion
Scientific title
A Pilot and Surgical Study of Larotrectinib for Treatment of Children With Newly-Diagnosed High-Grade Glioma With NTRK Fusion
Secondary ID [1] 0 0
CONNECT1903
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High Grade Glioma 0 0
Diffuse Intrinsic Pontine Glioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Larotrectinib
Treatment: Surgery - Larotrectinib surgical

Experimental: Feasibility Cohort - Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.

Experimental: Surgical Cohort - Larotrectinib administered PO, BID @100 mg/m2 3-5 days prior to definitive surgery, followed by Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.


Treatment: Drugs: Larotrectinib
Larotrectinib monotherapy x2 cycles followed by disease evaluation
Larotrectinib with or without chemotherapy backbone

Treatment: Surgery: Larotrectinib surgical
Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery followed by Larotrectinib monotherapy x2 cycles followed by disease evaluation
Larotrectinib with or without chemotherapy backbone
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Disease control rate
Timepoint [1] 0 0
At the end of Cycle 2 (each cycle is 28 days)
Primary outcome [2] 0 0
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Timepoint [2] 0 0
From Day 1 of treatment through 30 days following end of protocol treatment
Primary outcome [3] 0 0
Maximum Plasma Concentration [Cmax] of larotrectinib
Timepoint [3] 0 0
Days 1 through 5 of surgical cycle
Primary outcome [4] 0 0
Tumor Concentration of larotrectinib
Timepoint [4] 0 0
Day 5 of surgical surgical cycle
Secondary outcome [1] 0 0
Objective response rate (ORR)
Timepoint [1] 0 0
At the end of Cycle 2 (each cycle is 28 days)
Secondary outcome [2] 0 0
Survival rate
Timepoint [2] 0 0
From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Eligibility
Key inclusion criteria
- Age: Patients = 21 years of age (birth to 21 years of age) at the time of study
enrollment will be eligible.

- Diagnosis: Patients with newly-diagnosed high-grade (HGG), including diffuse intrinsic
pontine gliomas (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 high-grade glioma such as anaplastic
astrocytoma, glioblastoma, or H3 K27-mutant diffuse midline glioma verified at a
CONNECT site.

For sites that do not have CLIA-certified equivalent (certified laboratory) to assess NTRK
fusion, testing will be conducted centrally at NCH. NTRK testing will be performed by NGS
using targeted RNA-sequencing (Archer Solid Tumor analysis) Please submit 10 unstained
sections on charged slides at 10uM thickness, or 10 scrolls cut at 10uM thickness, along
with submission of an H&E slide. Formalin-fixed paraffin embedded (FFPE) tissue block and
FFPE tissue scroll specimens must contain minimum of 25% tumor Snap-frozen tissue specimens
are also acceptable and they must contain a minimum of 10% tumor. Please note that
turn-around time for this test is up to 21 days.

- 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.

- Surgical Cohort ONLY: Patients with newly-diagnosed HGG with NTRK fusions who have
undergone prior biopsy and for whom further resection is indicated for a more
definitive surgery at an enrolling site will be eligible to enroll onto the surgical
study. DIPG patients are not eligible for the surgical cohort.

- Performance Level: Karnofsky = 50% for patients > 16 years of age and Lansky = 50 for
patients = 16 years of age (See Appendix I). 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.

- Prior Therapy: Patients must not have received any prior anti-cancer chemotherapy.
Prior use of corticosteroids are allowed (see below
Minimum age
No limit
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria)

- Organ Function Requirements: Adequate Bone Marrow Function Defined as:

Peripheral absolute neutrophil count (ANC) = 1000/mm3 Platelet count = 100,000/mm3
(transfusion independent, defined as not receiving platelet transfusions for at least 7
days prior to enrollment) Hemoglobin >8 g/dL (may receive transfusions)

- Adequate Renal Function Defined as: Serum creatinine within normal institutional limits,
or Creatinine clearance or radioisotope GFR = 70ml/min/1.73 m2

- 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

- Adequate Pulmonary Function Defined as: Pulse oximetry > 94% on room air if there is
clinical indication for determination (e.g. dyspnea at rest).

- Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled
if on anticonvulsants and well controlled. See Section 5.5.2 and Appendix III for EIAED
guidelines.

- 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.



- 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.

- 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

- Infection: Patients must not have any active, uncontrolled systemic bacterial, viral
or fungal infection.

- Patients who have received prior solid organ transplantation are not eligible.

- Patients must not have malabsorption syndrome or other condition affecting oral
absorption.

- Patients must not be receiving any treatment with a strong cytochrome P450 3A4
(CYP3A4) inhibitor or inducer. (See Appendix III.) Strong inducers or inhibitors of
CYP3A4 should be avoided from 7 days prior to enrollment to the end of the study.

- 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 0
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/04/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2025
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Washington
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Canada
State/province [11] 0 0
Quebec
Country [12] 0 0
Germany
State/province [12] 0 0
Baden-Württemberg

Funding & Sponsors
Primary sponsor type
Other
Name
Nationwide Children's Hospital
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a pilot study that will evaluate disease status in children that have been newly
diagnosed high-grade glioma with TRK fusion. The evaluation will occur after 2 cycles of the
medication (Larotrectinib) have been given.

The study will also evaluate the safety of larotrectinib when given with chemotherapy in your
children; as well as the safety larotrectinib when given post-focal radiation therapy.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04655404
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Susan Chi, MD
Address 0 0
Dana Farber/ Boston Children's Cancer and Blood Disorders Center
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Leonie Mikael, PhD
Address 0 0
Country 0 0
Phone 0 0
16147223284
Fax 0 0
Email 0 0
LEONIE.MIKAEL@NATIONWIDECHILDRENS.ORG
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04655404

Additional trial details provided through ANZCTR
Accrual to date
Recruiting in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 21
Perth Children's Hospital
Recruitment hospital [2] 22
Sydney Children's Hospital
Recruitment hospital [3] 23
Queensland Children's Hospital
Recruitment postcode(s) [1] 26
6009
Recruitment postcode(s) [2] 27
2031
Recruitment postcode(s) [3] 28
4101
Funding & Sponsors
Primary sponsor
Other Collaborative groups
Primary sponsor name
Australia and New Zealand Children’s Haematology/Oncology Group (ANZCHOG)
Primary sponsor address
27-31 Wright Street, Clayton, VIC, 3168
Primary sponsor country
Australia
Ethics approval
Ethics application status
Approved
Ethics committee name [1] 26
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Address [1] 26
Level 7, Centre for Children's Health Research Queensland Children's Hospital Precinct, 62 Graham Street, South Brisbane, QLD 4101
Country [1] 26
Australia
Date submitted for ethics approval [1] 26
25/11/2019
Approval date [1] 26
09/01/2020
Ethics approval number [1] 26
HREC/19/QCHQ/59624
 
Public notes

Contacts
Principal investigator
Title 249 0
Prof
Name 249 0
Nick Gottardo
Address 249 0
Oncology and Haematology, 15 Hospital Avenue, Nedlands WA 6009
Country 249 0
Australia
Phone 249 0
+618 6456 0241
Fax 249 0
Email 249 0
Nick.Gottardo@health.wa.gov.au
Contact person for public queries
Title 250 0
Mrs
Name 250 0
Robyn Strong
Address 250 0
27-31 Wright Street, Clayton, VIC, 3168
Country 250 0
Phone 250 0
+613 8572 2684
Fax 250 0
+613 9902 4810
Email 250 0
Robyn.strong@hudson.org.au
Contact person for scientific queries
Title 251 0
Prof
Name 251 0
Nick Gottardo
Address 251 0
Oncology and Haematology, 15 Hospital Avenue, Nedlands WA 6009
Country 251 0
Australia
Phone 251 0
+618 6456 0241
Fax 251 0
Email 251 0
Nick.Gottardo@health.wa.gov.au