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A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors

PHASE2RECRUITING

FIREFLY-1 is an ongoing, Phase 2, multi center, open-label study to evaluate the safety and efficacy of oral pan-RAF inhibitor DAY101 in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade glioma or an advanced solid tumor harboring a known RAF alteration.

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Study details:

The study will consist of the following treatment arms:. Arm 1 (Low-Grade Glioma): Patients aged 6 months to 25 years, inclusive, with recurrent or progressive low-grade glioma harboring a known activating BRAF alteration, including BRAF V600 mutations and KIAA1549:BRAF fusions. Arm 2 (Low-Grade Glioma Expanded Access): Patients aged 6 months to 25 years, inclusive, with recurrent or progressive low-grade glioma harboring a known or expected to be activating RAF alteration (e.

g. , BRAF or CRAF/RAF1 fusion or BRAF V600 mutations). Opening of Arm 2 to enrollment will be based on the recommendation of the Data Safety Monitoring Board (DSMB).

Arm 3 (Advanced Solid Tumor): Patients aged 6 months to 25 years, inclusive, with advanced solid tumors harboring a known or expected to be activating RAF fusion (e. g. , BRAF or CRAF/RAF1 fusion).

Qualifying genomic alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories prior to enrollment into any of the aforementioned arms. Patients will be treated with DAY101, an oral pan-RAF inhibitor, for a planned period of 26 cycles will be treated with DAY101 for a planned period of 26 cycles (approximately 24 months). DAY101 will be administered at the recommended Phase 2 dose (RP2D) of 420 mg/m2 (not to exceed 600 mg) orally once weekly (QW) for each 28-day treatment cycle.

Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle. Patients will continue on DAY101 until radiographic evidence of disease progression by RANO (Arms 1 \& 2) or RECIST v1.

1 criteria (Arm 3) as determined by treating investigator, unacceptable toxicity, patient withdrawal of consent, or death. Patients who have radiographic evidence of disease progression may be allowed to continue DAY101 if, in the opinion of the investigator and approval by the Sponsor, the patient is deriving clinical benefit from continuing study treatment. Disease assessments for patients being treated beyond progression should continue as per regular schedule.

DAY101 is an oral pan-RAF inhibitor administered as an oral tablet at 420 mg/m2 (not to exceed 600 mg).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • Age 6 months to 25 years with:
  • Arms 1 & 2: a relapsed or progressive LGG with documented known activating BRAF alteration
  • Arm 3: locally advanced or metastatic solid tumor with documented known or expected to be activating RAF fusion
  • Confirmation of histopathologic diagnosis of LGG and molecular diagnosis of activating BRAF alteration
  • Must have received at least one line of systemic therapy and have evidence of radiographic progression
  • Must have at least 1 measurable lesion as defined by RANO (Arms 1 & 2) or RECIST v1.1 (Arm 3) criteria
  • Exclusion criteria

  • Patient's tumor has additional previously-known activating molecular alterations
  • Patient has symptoms of clinical progression in the absence of radiographic progression
  • Known or suspected diagnosis of neurofibromatosis type 1 (NF-1)
  • Other inclusion/exclusion criteria as stipulated by protocol may apply
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    Eligibility

    Age eligible for study : 6 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2021-04-22

    Primary completion: 2022-12-22

    Study completion finish: 2024-06-10

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

    trial

    Trial ID

    NCT04775485

    Intervention or treatment

    DRUG: DAY101

    Conditions

    • Low-grade Glioma
    • Advanced Solid Tumor

    Find a site

    Closest Location:

    Queensland Children's Hospital

    Research sites nearby

    Select from list below to view details:

    • Queensland Children's Hospital

      Brisbane, Not Specified, Australia

    • Royal Children's Hospital

      Parkville, Not Specified, Australia

    • Perth Children's Hospital

      Perth, Not Specified, Australia

    • Sydney Children's Hospital

      Randwick, Not Specified, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Arm #1
    • Pediatric patients with low-grade glioma treated with DAY101 (Registrational Arm)
    DRUG: DAY101
    • DAY101 is an oral pan-RAF inhibitor provided as an immediate-release tablet (100 mg) or powder for reconstitution (25 mg/mL).
    EXPERIMENTAL: Arm #2
    • Expanded access arm of pediatric patients with low-grade glioma treated with DAY101
    DRUG: DAY101
    • DAY101 is an oral pan-RAF inhibitor provided as an immediate-release tablet (100 mg) or powder for reconstitution (25 mg/mL).
    EXPERIMENTAL: Arm #3
    • Pediatric patients with advanced solid tumors treated with DAY101
    DRUG: DAY101
    • DAY101 is an oral pan-RAF inhibitor provided as an immediate-release tablet (100 mg) or powder for reconstitution (25 mg/mL).

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Arm 1: Overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteriaORR defined as the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by RANO criteriaUp to 48 months
    Arm 2: Assess the safety and tolerability of DAY101Type, frequency, and severity of treatment-emergent adverse events and laboratoryUp to 48 months
    Arm 3: Overall response rate (ORR) by independent radiology review committee (IRC) based on RECIST v1.1 criteriaMeasured by the proportion of patients with best overall confirmed response of CR or PR by RECIST v1.1 criteriaUp to 48 months

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Relationship between pharmacokinetics (PK) and drug effectsPharmacokinetic profile of DAY101 (e.g., area under the concentration-time curve \[AUC\], Cmin, etc.)Up to 48 months
    Effect on electrocardiogram (ECG) and QT interval corrected for heart rate by Fridericia's formula (QTcF) prolongationChange from baseline QT interval corrected for HR by Fridericia's formula (ΔQTcF); change from baseline PR interval (ΔPR); change from baseline QRS interval (ΔQRS); change from baseline heart rate (ΔHR); ECG waveform morphologyUp to 48 months
    ORR by InvestigatorMeasured by the proportion of patients with best overall confirmed response of CR or PR by RANO (Arms 1 \& 2) or RECIST (Arm 3) criteriaUp to 48 months
    Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay being evaluated by the SponsorMolecular analysis of cells obtained from archival tissueUp to 48 months
    Arm 1: Evaluate visual acuity (VA) outcomes compared with baselineMeasured by Teller Acuity Cards® IIUp to 48 months
    Arms 1 & 2: ORR by IRC and Investigator using RAPNO criteriaMeasured by the proportion of patients with best overall confirmed response of CR or PR by RAPNO-LGG criteriaUp to 48 months
    Arms 1 & 2: Progression free survival (PFS) using RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only)Measured by the time following initiation of DAY101 to progression or death in patients treated with DAY101Up to 48 months
    Arms 1 & 2: Duration of response (DOR) with best overall response of CR or PR using RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only)Measured by the length of response in patients with best overall confirmed response of CR or PR by RANO and RAPNO criteriaUp to 48 months
    Arms 1 & 2: Time to response following initiation of DAY101Measured by the time to first response following initiation of DAY101 in patients with best overall confirmed response of CR or PR by RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only)Up to 48 months
    Arms 1 & 2: Clinical benefit rate based on the proportion of patients with best overall response using RANO or RAPNO criteriaMeasured on the proportion of patients with best overall response of CR, PR, or SD lasting 12 months or more following initiation of DAY101 by 1) an IRC and 2) the treating Investigator (RANO only)Up to 48 months
    Arms 1 & 3: Assess the safety and tolerability of DAY101Type, frequency, and severity of treatment-emergent adverse events and laboratory abnormalitiesUp to 48 months
    Arm 3: Duration of response (DOR) with best overall response of CR or PR using RECIST v1.1 criteria by 1) an IRC and 2) the treating InvestigatorMeasured by the length of response in patients with best overall confirmed response of CR or PR by RECIST v1.1 criteriaUp to 48 months
    Arm 3: Time to response following initiation of DAY101Measured by the time to first response following initiation of DAY101 in patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria by 1) an IRC and 2) the treating InvestigatorUp to 48 months
    Arm 3: Clinical benefit rate based on the proportion of patients with best overall response using RECIST v1.1 criteriaMeasured on the proportion of patients with best overall response of CR, PR, or SD lasting 12 months or more following initiation of DAY101 by 1) an IRC and 2) the treating InvestigatorUp to 48 months

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    References

    Clinical Trials Gov: A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors

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