A Phase 3, Randomized, International Multicenter Trial of DAY101 Monotherapy Versus Standard of Care Chemotherapy in Patients with Pediatric Low-Grade Glioma Harboring an Activating RAF Alteration Requiring First-Line Systemic Therapy

See protocol section 1 - introduction

This study has been transitioned to CTIS with ID 2024-510742-13-00 check the CTIS register for the current data.

The primary objective is to compare the objective response rate (ORR) assessed
per Response Assessment in Neuro Oncology for low-grade gliomas (RANO-LGG)
criteria by Independent Review Committee (IRC) of tovorafenib monotherapy
versus standard of care (SoC) chemotherapy in patients with pediatric low-grade
glioma harboring an activating rapidly accelerated fibrosarcoma gene (RAF)
alteration requiring first line systemic therapy.

This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 study to
evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy
versus SoC chemotherapy in patients with pediatric low-grade glioma harboring
an activating RAF alteration requiring first-line systemic therapy. Patients
with RAF alterations will be identified through molecular assays as routinely
performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other
similarly certified laboratories. Approximately 400 treatment naïve low-grade
glioma patients will be randomized 1:1 to either tovorafenib (Arm 1) or an
Investigator*s choice of SoC chemotherapy (Arm 2). Randomization will be
stratified by primary location of the tumor (supratentorial midline vs. other),
type of genomic alteration (fusion vs. mutation), CDKN2A status (deletion vs.
wild type/unknown), and infant CHG diagnosis (yes vs. no).
This study consists of a Screening phase, a treatment phase, an End of
Treatment (EOT) Visit, a 30-Day Safety Follow-Up (SFU) visit, and a long-term
follow-up (LTFU) period. Upon completion of study treatment, ongoing safety,
disease stability/progression, survival status, and subsequent anticancer
therapies will be assessed in the LTFU period. For each patient, study
participation is up to 5 years, inclusive of the treatment phase and a LTFU
period.
Arm 1 (tovorafenib): Treatment cycles will repeat every 28 days in the absence
of disease progression. Patients will continue tovorafenib until any of the
following occurs: disease progression based on RANO LGG criteria, unacceptable
toxicity, withdrawal of consent to treatment, or end of study.
Arm 2 (Investigator*s Choice of SoC Chemotherapy): Patients will receive 1 of 3
SoC chemotherapy options selected by the treating Investigator: Children*s
Oncology Group - Vincristine/Carboplatin (COG-V/C) regimen, International
Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin
(SIOPe-LGG-V/C) regimen, or vinblastine (VBL) regimen. The choice of SoC
chemotherapy regimen will be selected prior to patient randomization. Treatment
will continue until completion of therapy or until any of the following occurs:
disease progression based on RANO-LGG criteria, unacceptable toxicity,
withdrawal of consent to treatment, or end of study.
Patients who discontinue treatment due to disease progression will have (1)
radiographic evidence of progressive disease based on RANO-LGG, as determined
by the Investigator and confirmed by the IRC, or (2) clinical progression based
on RANO-LGG criteria determined by the Investigator. Investigators are
encouraged to discuss cases of clinical progression and early radiographic
progression without clinical symptom with the Sponsor Medical Monitor prior to
treatment discontinuation or initiation of a different form of treatment for
the malignancy. Patients may continue therapy beyond progressive disease per
Section 5.3 (of the protocol).

DAY101 is provided as both oral tablet and powder for reconstitution
formulations.
Vincristine is provided as a solution for injection, carboplatin is provided as
a concentrate for solution for infusion, and VBL is provided as a solution for
injection.

Patients will be initiated on study treatment of DAY101 or SoC chemotherapy
after randomization. The choice of SoC chemotherapy regimen the patient would
receive in this study (COG-V/C, SIOPe-LGG-V/C, or VBL) will be selected prior
to patient randomization.
Arm 1 (DAY101): Patients enrolled in Arm 1 will be initiated on once weekly
dosing of DAY101 at 420 mg/m2 (not to exceed 600 mg) starting C1D1 according to
the patient*s baseline body surface area (BSA). Treatment cycles will repeat
every 28 days and DAY101 will be administered on Days 1, 8, 15, and 22 of each
28-day cycle (4 week cycle).
Arm 2 (COG-V/C): During induction (first 12 weeks), vincristine is given weekly
during Week 1 to Week 10. Carboplatin is given on Weeks 1, 2, 3, 4, 7, 8, 9,
and 10. Patient will not receive treatment for the last 2 weeks of induction.
During maintenance, vincristine and carboplatin are given in repeating cycles
until completion of 60 weeks of therapy (8 maintenance cycles): vincristine on
Weeks 1, 2, and 3 and carboplatin on Weeks 1, 2, 3, and 4. Note: Each cycle
during maintenance is 6 weeks (42 days).
Arm 2 (SIOPe-LGG-V/C): During induction (first 24 weeks, first 7 cycles),
vincristine is given weekly during Week 1 to Week 10, and on Weeks 13, 17, and
21. Carboplatin is given on Weeks 1, 4, 7, 10, 13, 17, and 21. During
consolidation, vincristine and carboplatin are given in repeating cycles until
completion of 81 weeks of therapy: vincristine on Weeks 1, 2, and 3 8, and 15
and carboplatin on Week 1. Note: Each cycle during consolidation is 6 weeks (42
days).
Arm 2 (VBL): Vinblastine is given weekly, and treatment will continue until
completion of 70 weeks of therapy, radiographic progression, or unacceptable
toxicity. One cycle is defined as 28 days (4 weeks).

Tumors will be assessed by radiographic tumor measurements using MRI of the
brain and/or spine.
Adaptive behaviors will be evaluated using the Vineland III Adaptive Behavior
Scale (VABS).
Standard monitoring for safety is outlined in the protocol and will include
physical examination, neurological examination, dermatology examination, bone
assessment (Tanner stage < 4-5), Karnofsky/Lansky score, cardiac function,
clinical adverse events (AEs), laboratory variables (eg, hematology and serum
chemistries), and vital signs.
Patients with an underlying visual function deficit related to the primary
malignancy or OPG will have a visual acuity examination at Screening, every
radiographic response assessment, EOT Visit, and continue every 6 months during
LTFU (Arm 1 and Arm 2).
In patients 2 years of age or older, Health-Related Quality of Life will be
assessed using the Pediatrics Quality of Life**Core (PedsQL Core), Pediatrics
Quality of Life**Cancer (PedsQL-Cancer), and PROMIS® assessment for the patient
or parent/caregiver.

Risks associated with study drug administration as explained above in Section
E9. What risks does participation involve for human subjects?

Risks and discomforts associated with study procedures are as follows:
Many of the tests in this study, such as an MRI, are regularly done as a part
of standard treatment for this type of tumor. However, these tests may be done
more frequently during this study.
- Biopsy: Only in patients for whom an archival tumor tissue sample is not
available. A biopsy involves the removal of a small amount of tissue from the
tumor so that it can be examined. The sample may be removed from the tumor by a
needle biopsy, which involves the insertion of a needle into the precise area
of the tumor, usually using x-ray guidance. Although both surgical biopsy or
needle biopsy are usually safe, there are some potential risks: swelling or
bleeding, infection, blood clots, reaction to anesthesia.
- MRI: MRI scans use powerful magnets, and some MRI scanners are very narrow.
With a certain type of dye used for MRI scans, some patients with kidney
disease may have a severe reaction of skin thickening, joint pain and/or
swelling, and in rare cases, lung, and heart problems and even death. Sedation
or anesthesia may be required for a MRI, which have their own side effects.
- X-ray: This test uses a machine to allow light to pass through the body to
create a picture inside for the investigator to see. This test will be done to
check the patient's bones in the wrist/hand. The patient should stay very still
while the test is being done, which may feel uncomfortable.
- Blood Samples: Side effects of having blood taken may include pain, redness,
swelling, and/or bruising where the needle enters the body. Rare instances of
fainting, excess bleeding, blood clotting, or infection have occurred.
- Electrocardiograms: To perform the test, sticky patches (electrodes) will be
placed on the skin to record the patient's heart*s activity. the patient may
feel some discomfort when the technician removes the adhesive patches after the
procedure, similar to pulling off an adhesive bandage. The adhesive patches can
also cause skin irritation or rash in some patients.
- Echocardiogram (ECHO): There are no risks expected from ECHO.