Tovorafenib (DAY101) Monotherapy for Patients With Melanoma and Other Solid Tumors

A Phase 2, Subprotocol of DAY101 Monotherapy for Patients With Recurrent, Progressive, or Refractory Solid Tumors With MAPK Pathway Aberrations

This is a Phase 2, multi-center, open-label to evaluate the efficacy and safety of tovorafenib (DAY101) in participants ≥12 years of age with recurrent or progressive melanoma or solid tumors with BRAF fusion or CRAF/RAF1 fusions or amplification.

Study Overview

• Status: Terminated
• Conditions: Melanoma; Colorectal Cancer; Solid Tumor; Non Small Cell Lung Cancer; Bladder Cancer; Thyroid Cancer, Papillary; Pilocytic Astrocytoma; Bladder Urothelial Carcinoma; Non-Small Cell Adenocarcinoma; Pancreatic Acinar Carcinoma; RAF Mutation; CRAF Gene Amplification; RAF1 Gene Amplification; BRAF Gene Fusion; BRAF Fusion; CRAF Gene Fusion; CRAF Fusion; RAF1 Gene Fusion; RAF1 Fusion; Spitzoid Melanoma; Pilocytic Astrocytoma, Adult; Spitzoid Malignant Melanoma; MAP Kinase Family Gene Mutation
• Intervention / Treatment: Drug: Tovorafenib

Detailed Description

Study DAY101-102 (master study) and sub-studies will consist of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period where survival, status and subsequent anticancer therapies are collected.

Tovorafenib will be evaluated alone or combined with a different targeted therapy in each sub-study. The Phase 1b part of each applicable sub-study will evaluate the safety of the combination and select the dose for the Phase 2 part. The Phase 2 part of each sub-study will evaluate anti-tumor activity.

Substudy A will enroll patients with recurrent or progressive melanoma or other solid tumors with BRAF fusion or CRAF/RAF1 fusions or amplification.

Substudy B will enroll patients with recurrent or progressive melanoma or other solid tumors with alterations in the key proteins of the MAPK pathway.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia
      • Monash Medical Centre
• Belgium
  • Edegem, Belgium
    • Antwerp University Hospital
• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • The Hospital for Sick Children
    • Toronto, Ontario, Canada
      • Princess Margaret Cancer Centre
• France
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France
      • Hopital de la Timone - APHM
• South Korea
  • Busan, South Korea
    • Dong-A University Hospital
  • Seoul, South Korea
    • Asan Medical Center
  • Seoul, South Korea
    • Samsung Medical Center
  • Seoul, South Korea
    • Severance Hospital, Yonsei University Health System
• Spain
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain
    • Hospital Clinic Barcelona
  • Madrid, Spain
    • Hospital Universitario Ramon y Cajal
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic
    • Newport Beach, California, United States, 92663
      • Hoag Health
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Cancer Specialists of North Florida
  • Indiana
    • Indianapolis, Indiana, United States, 46250
      • Community North Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • OHSU Knight Cancer Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Hillman Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent by participants ≥ 12 years of age either a Consent or an Assent Form will be provided to the patient based on their capacity, local regulations, and guidelines.
• Participants must have a histologically confirmed diagnosis of melanoma or other solid tumor and a BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplifications obtained through a tumor or liquid biopsy as assessed by genomic sequencing, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or another clinically accepted molecular diagnostic method recognized by local laboratory or regulatory agency.
• Participants must have radiographically-recurrent or radiographically-progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1 or RANO).
• Archival tumor tissue (preferably less than 3 years old) or fresh tumor tissue for correlative studies is required
• If brain metastases are present, they must have been previously treated and be stable as assessed by radiographic imaging

Exclusion Criteria:

• Prior therapy of any RAS-, RAF-, MEK-, or ERK-directed inhibitor therapy
• Known presence of concurrent activating mutation
• Participants with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melanoma Cohort; Tovorafenib monotherapy	Drug: Tovorafenib; Tovorafenib tablet for oral use.; Other Names: DAY101
Experimental: Tissue Agnostic Cohort; Tovorafenib monotherapy	Drug: Tovorafenib; Tovorafenib tablet for oral use.; Other Names: DAY101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) by the Investigator	ORR was defined as the percentage of participants with the best overall confirmed response of complete response (CR) or partial response (PR) according to the appropriate response assessment criteria including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) for the disease setting as assessed by the Investigator. CR or PR was confirmed at a subsequent scan (>=4 weeks) if the criteria for each are met . The exact 95% confidence intervals (CIs) were calculated using Clopper-Pearson method.	Up to 23 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An serious adverse event (SAE) is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. An AE is considered to be treatment-emergent if it has a start date/time on or after the first administration of study drug until 30 days after the last dose of study drug and before the start of subsequent therapy, whichever comes earlier. The distribution of AEs was analyzed by the type, frequency and severity for TEAEs.	Up to 23 months
Number of Participants With Worst Case Hematology Results by Maximum Grade Increase Post-baseline Relative to Baseline	Blood samples were collected for the analysis of following hematology parameters: anemia, neutrophil count decreased and white blood cell decreased. Grade 1 (G1): mild; Grade 2 (G2): moderate; Grade 3 (G3): severe; Grade 4 (G4) life-threatening or disabling. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Any worst-case post baseline increase to G2, G3, and G4 are presented. The laboratory parameters were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.	Baseline and up to 23 months
Number of Participants With Worst Case Chemistry Results by Maximum Grade Increase Post-baseline Relative to Baseline	Blood samples were collected for the analysis of following chemistry parameters: creatine phosphokinase (CPK) increased, hypokalemia, hypoalbuminemia, hypercalcemia, hypocalcemia and hyponatremia. Grade 1 (G1): mild; Grade 2 (G2): moderate; Grade 3 (G3): severe; Grade 4 (G4) life-threatening or disabling. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Any worst-case post baseline increase to G2, G3, and G4 are presented. The laboratory parameters were graded according to CTCAE version 5.	Baseline and up to 23 months
Duration of Response (DOR) in Participants With Best Overall Response	Duration of response was defined as the interval from the date of the first documentation of tumor response (CR or PR) that was subsequently confirmed by investigator assessment to the date of first occurrence of radiographic disease progression based on RECIST 1.1 or RANO criteria or death due to any cause, whichever occurs earlier. DOR was estimated using Kaplan-Meier method.	Up to 23 months
Duration of Progression Free Survival	Progression free survival was defined as the interval from the date of the first dose to the first occurrence of radiographic disease progression based on RECIST 1.1 or RANO criteria or death due to any cause, whichever occurs earlier. Progression free survival was estimated using Kaplan-Meier method.	Up to 23 months
Duration of Overall Survival	Overall survival is defined as the interval from the date of the first dose until the recorded date of death due to any cause. Overall survival was estimated using Kaplan-Meier method.	Up to 23 months
Time to Response	Time to Response was defined in participants with best overall response of complete response or partial response as determined by Investigator. It is the interval from the date of the first dose to date of first documentation of tumor response that was subsequently confirmed by investigator assessment.	Up to 23 months

Collaborators and Investigators

• Sponsor: Day One Biopharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2021
• Primary Completion (Actual): July 8, 2024
• Study Completion (Actual): July 8, 2024

Study Registration Dates

• First Submitted: June 23, 2021
• First Submitted That Met QC Criteria: July 30, 2021
• First Posted (Actual): August 2, 2021

Study Record Updates

• Last Update Posted (Estimated): October 2, 2025
• Last Update Submitted That Met QC Criteria: September 12, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: BRAF fusion; CRAF/RAF1 fusion; CRAF/RAF1 amplification
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Diseases; Thyroid Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lung Neoplasms; Skin Diseases; Urologic Neoplasms; Carcinoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Urinary Bladder Diseases; Thyroid Diseases; Adenocarcinoma, Papillary; Skin and Connective Tissue Diseases; Thyroid Cancer, Papillary; Colorectal Neoplasms; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung; Melanoma; Urinary Bladder Neoplasms; Astrocytoma; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; tovorafenib
• Other Study ID Numbers: DAY101-102a; 2021-003768-29 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No