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JOURNAL ONKOLOGIE – STUDIE

CONNECT1903 A Pilot Study of Larotectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion

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NCT-Nummer:
NCT04655404

Studienbeginn:
Februar 2021

Letztes Update:
17.12.2020

Wirkstoff:
Larotrectinib

Indikation (Clinical Trials):
Glioma

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Frühphase (Phase 0)

Sponsor:
Nationwide Children's Hospital

Collaborator:
-

Kontakt

Studienlocations (3 von 18)

Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
69120 Heidelberg
(Baden-Württemberg)
Germany» Google-Maps
Ansprechpartner:
Olaf Witt, MD
Phone: 49 6221 42 3570
E-Mail: o.witt@kitz-heidelberg.de
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Studien-Informationen

Detailed Description:

In this pilot study, we will assess the disease control rate (Continued Complete

Response-CCR, Complete Response-CR, Partial Response-PR and Stable Disease-SD) as well as

survical rate (overall survival- OS and progression free survival- PFS) in children with

newly diagnosed HGG with TRK fusion who receive 2 cycles of larotrectinib monotherapy

administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule. After

2 monotherapy cycles of larotrectinib, patients with CCR or CR will continue to receive

larotrectinib maintenance therapy as monotherapy for a total of 12 cycles. Patients ≤ 48

months with PR or SD after 2 cycles of larotrectinib will go on to receive combination

therapy with standard backbone chemotherapy (BABYPOG or HIT-SKK). Patients > 48 months of age

(or patients ≥ 36 months of age, or patients with DIPG >18 months of age, at the discretion

of the local investigator) will receive focal radiation therapy. A surgical cohort study will

be explored whereby patients who have had a tumor biopsy/partial resection at their local

institution and are planned to subsequently undergo definitive resection will receive 3-5

days (6-10 doses) of larotrectinib pre-surgery.

The study design of this trial requires 15 patients evaluable for disease control and for

safety/ toxicity of larotrectinib as monotherapy. The surgical cohort will enroll up to 4

patients and will count towards the total 15 evaluable patients. A minimum of 6 patients will

be evaluable for safety toxicity of larotrectinib in combination with standard-of-care

chemotherapy or radiotherapy.

Ein-/Ausschlusskriterien

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 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 Cardiac Function Defined as: Shortening fraction of ≥27% by echocardiogram, or

Ejection fraction of ≥ 50% by gated radionuclide study.

- 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.

Exclusion Criteria:

- 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.

Studien-Rationale

Primary outcome:

1. Disease control rate (Time Frame - 24 months):
To assess the disease control rate of larotrectinib in young children with newly-diagnosed high-grade glioma with NTRK fusion after 2 cycles of larotrectinib monotherapy

2. Incidence of Treatment- Emergent Adverse Events (Safety) of larotrectinib (Time Frame - 24 months):
To assess the safety of larotrectinib when given in combination with chemotherapy or post-focal radiation therapy, assessed by CTCAE v5.0

3. Measurement of Are Under the Curve (AUC) of larotrectinib (Time Frame - 24 months):
To characterize the area under the plasma concentration versus time curve (AUC) of larotrectinib in surgical patients through the measurement of blood pharmacokinetics

4. Dose-response relationship of larotrectinib (Time Frame - 24 months):
To characterize the dose-response relationship of larotrectinib in surgical patients through the measurement of blood pharmacodynamics

Secondary outcome:

1. Response rate (Time Frame - 24 months):
To assess the objective response rate (ORR) (Complete Response [CR] and Partial Response [PR]) of larotrectinib in children with newly-diagnosed high-grade glioma with NTRK fusion after 2 cycles of larotrectinib monotherapy.

2. Survival rate (Time Frame - 60 months):
To assess overall (OS) and progression-free survivals (PFS) of children with high-grade gliomas treated with a larotrectinib-containing regimen at 1, 3 and 5 years defined as date of death or earliest date of failure.

Geprüfte Regime

  • Larotrectinib:
    Larotrectinib monotherapy x2 cycles followed by disease evaluation
  • Larotrectinib:
    Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery

Quelle: ClinicalTrials.gov


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