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

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ClinicalTrials.gov Identifier: NCT04655404
Recruitment Status : Recruiting
First Posted : December 7, 2020
Last Update Posted : April 21, 2021
Sponsor:
Information provided by (Responsible Party):
Nationwide Children's Hospital

Tracking Information
First Submitted Date  ICMJE November 9, 2020
First Posted Date  ICMJE December 7, 2020
Last Update Posted Date April 21, 2021
Actual Study Start Date  ICMJE April 8, 2021
Estimated Primary Completion Date December 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2020)
  • 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
  • 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
  • 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
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2020)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pilot Study of Larotectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion
Official Title  ICMJE A Pilot and Surgical Study of Larotrectinib for Treatment of Children With Newly-Diagnosed High-Grade Glioma With NTRK Fusion
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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE High Grade Glioma
Intervention  ICMJE
  • Drug: Larotrectinib
    Larotrectinib monotherapy x2 cycles followed by disease evaluation
  • Procedure: Larotrectinib
    Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery
Study Arms  ICMJE Experimental: Larotrectinib
Larotrectinib will be administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule.
Interventions:
  • Drug: Larotrectinib
  • Procedure: Larotrectinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 30, 2020)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2025
Estimated Primary Completion Date December 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Dorothy Crabtree 6147228693 Dorothy.Crabtree@nationwidechildrens.org
Contact: Karina Woodling 614-722-3733 Karina.Woodling@nationwidechildrens.org
Listed Location Countries  ICMJE Australia,   Canada,   Germany,   Netherlands,   United Kingdom,   United States
Removed Location Countries Austria
 
Administrative Information
NCT Number  ICMJE NCT04655404
Other Study ID Numbers  ICMJE STUDY00001275
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nationwide Children's Hospital
Study Sponsor  ICMJE Nationwide Children's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Susan Chi, MD Dana Farber/ Boston Children's Cancer and Blood Disorders Center
Study Chair: Maryam Fouladi Nationwide Children's Hospital
PRS Account Nationwide Children's Hospital
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP