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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04655404

Studienbeginn:
April 2021

Letztes Update:
08.08.2024

Wirkstoff:
Larotrectinib

Indikation (Clinical Trials):
Glioma, Diffuse Intrinsic Pontine Glioma

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Frühphase (Phase 0)

Sponsor:
Nationwide Children's Hospital

Collaborator:
-

Studienleiter

Susan Chi, MD
Study Chair
Dana Farber/ Boston Children's Cancer and Blood Disorders Center
Maryam Fouladi, MD
Study Chair
Nationwide Children's Hospital

Kontakt

Studienlocations
(3 von 16)

Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
69120 Heidelberg
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Olaf Witt, MD
Phone: 49 6221 42 3570
E-Mail: o.witt@kitz-heidelberg.de» Ansprechpartner anzeigen
Children's National Medical Center
20010 Washington
United StatesNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Eugene Hwang, MD
Phone: 202-476-5046
E-Mail: ehwang@childrensnational.org» Ansprechpartner anzeigen
Ann & Robert H. Lurie Children's Hospital of Chicago
60611 Chicago
United StatesNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Ashley Plant, MD
Phone: 312-227-4090
E-Mail: Aplant@luriechildrens.org» Ansprechpartner anzeigen
Montreal Children's Hospital
H4A3J1 Montréal
CanadaRekrutierend» Google-Maps
Ansprechpartner:
Genevieve Legault, MD
Phone: 514-412-4400
Phone (ext.): 60497
E-Mail: Genevieve.legault4@mcgill.ca» Ansprechpartner anzeigen
Alle anzeigen

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

survival 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.

Continuation of treatment beyond 12 cycles, and up to 24 cycles, may be considered for

patients on Larotrectinib monotherapy if they are receiving clinical benefit from the

study, at the discretion of the treating physician.

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 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 - At the end of Cycle 2 (each cycle is 28 days)):
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 newly diagnosed with HGG carrying NTRK fusion after 2 cycles of larotrectinib monotherapy.

2. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 (Time Frame - From Day 1 of treatment through 30 days following end of protocol treatment):
To assess the safety and tolerability of larotrectinib given in combination with chemotherapy or post-focal radiation therapy in young children newly diagnosed with HGG carrying NTRK fusion. This will be achieved by calculating the number of participants with, as well as frequency and severity of, larotrectinib-related Adverse Events as assessed by CTCAE v5.0.

3. Maximum Plasma Concentration [Cmax] of larotrectinib (Time Frame - Days 1 through 5 of surgical cycle):
To characterize the plasma pharmacokinetics (PK) of larotrectinib in children newly diagnosed with HGG carrying NTRK fusions who undergo a second definitive resection. This will be achieved by measuring the Maximum Plasma Concentration (Cmax) of larotrectinib in blood (plasma) samples collected at pre-dose (day -5), pre-surgery (day -1) and during surgery.

4. Tumor Concentration of larotrectinib (Time Frame - Day 5 of surgical surgical cycle):
To characterize the tumor pharmacokinetics (PK) of larotrectinib in children newly diagnosed with HGG carrying NTRK fusions who undergo a second definitive resection by measuring the concentration of larotrectinib in tumor tissue collected on day 5 of surgical cycle

Secondary outcome:

1. Objective response rate (ORR) (Time Frame - At the end of Cycle 2 (each cycle is 28 days)):
To assess the objective response rate (ORR) (Complete Response [CR] and Partial Response [PR]) of larotrectinib in children newly-diagnosed with HGG carrying NTRK fusion after 2 cycles of larotrectinib monotherapy.

2. Survival rate (Time Frame - 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):
To assess overall (OS) and progression-free survivals (PFS) of children newly diagnosed with HGG carrying NTRK fusion treated with a larotrectinib-containing regimen at 1, 3 and 5 years and compared to historical data from BABYPOG and HIT-SKK.

Studien-Arme

  • 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.

Geprüfte Regime

  • Larotrectinib:
    1. Larotrectinib monotherapy x2 cycles followed by disease evaluation 2. Larotrectinib with or without chemotherapy backbone
  • Larotrectinib surgical:
    1. Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery followed by Larotrectinib monotherapy x2 cycles followed by disease evaluation 2. Larotrectinib with or without chemotherapy backbone

Quelle: ClinicalTrials.gov


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