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

Official title

FIREFLY-1: A Phase 2, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Pan-RAF Inhibitor DAY101 in Pediatric Patients With RAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced Solid Tumors

Overview

This is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of Type II RAF (tovorafenib) in pediatric participants with low-grade glioma or advanced solid tumors. 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 arms. The study will consist of a screening period, a treatment period, a long-term extension phase, end of treatment (EOT) visit(s), a safety follow-up visit, and long-term follow-up assessments.

Interventions

• Drug Tovorafenib
  Tovorafenib is an oral Type II RAF kinase inhibitor available in 100 mg immediate-release tablet or 25 mg/milliliter (mL) powder for reconstitution.

Primary outcome measures

• Arm 1: Overall response rate [Time frame: Up to 48 months]
• Arm 2: Number of participants reporting adverse events [Time frame: Up to 48 months]
• Arm 2: Number of participants with clinically significant changes in clinical chemistry parameters [Time frame: Up to 48 months]
• Arm 2: Number of participants with clinically significant changes in hematology parameters [Time frame: Up to 48 months]
• Arm 3: Overall response rate [Time frame: Up to 48 months]

Secondary outcome measures (12)

• Arm 1 and 3: Number of participants reporting adverse events [Time frame: Up to 48 months]
• Arm 1 and 3: Number of participants with clinically significant changes in clinical chemistry parameters [Time frame: Up to 48 months]
• Arm 1 and 3: Number of participants with clinically significant changes in hematology parameters [Time frame: Up to 48 months]
• Arm 1: Area under the concentration-time curve (AUC) of Tovorafenib [Time frame: Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1]
• Arm 1: Minimum drug concentration (Cmin) [Time frame: Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1]
• Arm 1: Change from Baseline QT interval corrected for heart rate by Fridericia's formula (ΔQTcF) [Time frame: Baseline to 48 months]
• Arm 1: Change from Baseline PR interval (ΔPR) [Time frame: Baseline to 48 months]
• Arm 1: Change from Baseline QRS interval (ΔQRS) [Time frame: Baseline to 48 months]
• Arm 1: Change from baseline heart rate (ΔHR) [Time frame: Baseline to 48 months]
• Arm 1: Change in electrocardiogram (ECG) waveform morphology [Time frame: Baseline to 48 months]
• Arm 1 and Arm 2: Overall response rate [Time frame: Up to 48 months]
• Arm 1, Arm 2 and Arm 3: Overall response rate in Pediatric participants [Time frame: Up to 48 months]

Eligibility criteria

Inclusion criteria

• Low Grade Glioma \& Low-Grade Glioma Extension: a relapsed or progressive LGG with documented known activating BRAF alteration.
• Advanced Solid Tumor: locally advanced or metastatic solid tumor with documented known or expected to be activating RAF fusion.
• Participants must have histopathologic verification of malignancy at either original diagnosis or relapse.
• Must have received at least one line of prior systemic therapy and have documented 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

• Participant's tumor has additional previously-known activating molecular alterations.
• Participant has symptoms of without radiographically recurrent or radiographically progressive disease.
• Known or suspected diagnosis of neurofibromatosis type 1 (NF-1) via genetic testing or current diagnostic criteria.

Other inclusion/exclusion criteria as stipulated by protocol may apply

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 14 centers

• UCSF Benioff Children's Hospital — San Francisco
• Children's National Medical Center — Washington D.C.
• Lurie Children's Hospital of Chicago — Chicago
• Johns Hopkins Hospital — Baltimore
• Dana-Farber Cancer Institute — Boston
• CS Mott Children's Hospital — Ann Arbor
• St. Louis Children's Hospital — St Louis
• NYU Langone Health — New York
• … and 6 more centers

Australia · 5 centers

• Queensland Children's Hospital — Brisbane
• Royal Children's Hospital — Parkville
• Perth Children's Hospital — Perth
• Sydney Children's Hospital — Randwick
• The Children's Hospital at Westmead — Westmead

Canada · 3 centers

• Centre Hospitalier Universitaire Ste-Justine — Montreal
• Montreal Children's Hospital — Montreal
• Centre Mère-Enfant Soleil du CHU — Québec

Israel · 3 centers

• Rambam Health Care Campus — Haifa
• Schneider Children's Medical Center of Israel — Petah Tikva
• The Chaim Sheba Medical Center — Ramat Gan

Germany · 2 centers

• Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Otto-Heubner-Centrum für Kind — Berlin
• Hopp-Kindertumorzentrum Heidelberg (KiTZ), KiTZ Clinical Trial Unit (ZIPO) — Heidelberg

South Korea · 2 centers

• Seoul National University Hospital — Seoul
• Severance Hospital - Yonsei University — Seoul

United Kingdom · 2 centers

• UCL Great Ormond Street Institute of Child Health — London
• Newcastle University — Newcastle upon Tyne

Denmark · 1 center

• Rigshospitalet — Copenhagen

Netherlands · 1 center

• Princess Maxima Center for Pediatric Oncology — Utrecht

Singapore · 1 center

• KK Women's and Children's Hospital — Singapore

Switzerland · 1 center

• Universitäts-Kinderspital Zürich - Eleonorenstiftung — Zurich

Publications

• Kilburn LB, Khuong-Quang DA, Hansford JR, Landi D, van der Lugt J, Leary SES, Driever PH, Bailey S, Perreault S, McCowage G, Waanders AJ, Ziegler DS, Witt O, Baxter PA, Kang HJ, Hassall TE, Han JW, Hargrave D, Franson AT, Yalon Oren M, Toledano H, Larouche V, Kline C, Abdelbaki MS, Jabado N, Gottardo NG, Gerber NU, Whipple NS, Segal D, Chi SN, Oren L, Tan EEK, Mueller S, Cornelio I, McLeod L, Zhao PMID 37978284

Identifiers

NCT: NCT04775485 · DAY101-001/PNOC026

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗