Tovorafenib (DAY101) Monotherapy or in Combination With Other Therapies for Patients With Melanoma and Other Solid Tumors

A Phase 1b/2, Open Label Study of DAY101 Monotherapy or Combination With Other Therapies for Patients With Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations

This is a Phase 1b/2, multi-center, open label umbrella study of patients ≥12 years of age with recurrent, progressive, or refractory melanoma or other solid tumors with alterations in the key proteins of the RAS/RAF/MEK/ERK pathway, referred to as the MAPK pathway.

Study Overview

• Status: Recruiting
• 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; MEK Mutation; RAS Mutation; 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; Drug: Pimasertib

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.

(Closed to Enrollment) 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 (Estimated): 168
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Day One Biopharmaceuticals; Phone Number: 650-484-0899; Email: clinicaltrials@dayonebio.com

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia
      • Active, not recruiting
      • Monash Medical Centre
• Belgium
  • Edegem, Belgium
    • Active, not recruiting
    • Antwerp University Hospital
• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Recruiting
      • The Hospital for Sick Children
    • Toronto, Ontario, Canada
      • Recruiting
      • Princess Margaret Cancer Centre
• France
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France
      • Active, not recruiting
      • Hopital de La Timone - APHM
• Korea, Republic of
  • Busan, Korea, Republic of
    • Active, not recruiting
    • Dong-A University Hospital
  • Seoul, Korea, Republic of
    • Active, not recruiting
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Active, not recruiting
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Active, not recruiting
    • Severance Hospital, Yonsei University Health System
• Spain
  • Barcelona, Spain
    • Active, not recruiting
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain
    • Active, not recruiting
    • Hospital Clinic Barcelona
  • Madrid, Spain
    • Active, not recruiting
    • Hospital Universitario Ramón y Cajal
• United States
  • California
    • Los Angeles, California, United States, 90025
      • Recruiting
      • The Angeles Clinic
      • Contact: Saba Mukarram; Phone Number: 310-231-2181; Email: smukarram@theangelesclinic.org
    • Newport Beach, California, United States, 92663
      • Recruiting
      • Hoag Health
      • Contact: Wendy Price; Phone Number: 949-764-4510; Email: wendy.price@hoag.org
      • Contact: Clinical Research Main Line; Phone Number: 949-764-5543
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Active, not recruiting
      • University of Colorado Hospital
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Recruiting
      • Cancer Specialists of North Florida
      • Contact: Mary Alice Anderson; Email: maryalice.anderson@csnf.us
    • Miami, Florida, United States, 33136
      • Withdrawn
      • Sylvester Comprehensive Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46250
      • Recruiting
      • Community North Cancer Center
      • Contact: Betsy Glowinski; Phone Number: 317-497-2836; Email: eglowinski@ecommunity.com
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • OHSU Knight Cancer Institute
      • Contact: Knight Clinical Trials Information Line; Phone Number: 503-494-1080; Email: Phase1@ohsu.edu; trials@ohsu.edu
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC Hillman Cancer Center
      • Contact: Immunotherapy and Drug Development Center; Email: IDDCReferrals@upmc.edu
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • 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 patients ≥ 18 years of age and, assent for patients ≥ 12 up to < 18 years of age
• Patients must have radiographically-recurrent or radiographically-progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1)
• 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

(Closed to Enrollment) Substudy A-specific inclusion criterion:

• Patients must have a report of histologically confirmed diagnosis of melanoma or other solid tumor and a concurrent BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplification 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 agency.

Substudy B-specific inclusion criterion:

• Patients must have a report of histologically confirmed diagnosis of melanoma or other solid tumor and a concurrent MAPK pathway alteration (genomic alterations in RAS, RAF, MEK, or NF1) through a tumor or liquid biopsy as assessed by genomic sequencing, PCR, FISH, or another clinically accepted molecular diagnostic method recognized by local laboratory or agency.

Exclusion Criteria:

• Known presence of concurrent activating mutation
• Patients with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO)

(Closed to Enrollment) Substudy A-specific exclusion criterion:

• Prior therapy of any RAS- RAF-, MEK-, or ERK-directed inhibitor therapy

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: Arm #2; Tovorafenib plus pimasertib	Drug: Tovorafenib; Tovorafenib tablet for oral use.; Drug: Pimasertib; Pimasertib capsule for oral use.
Experimental: Arm #1 (Closed to Enrollment); Tovorafenib monotherapy	Drug: Tovorafenib; Tovorafenib tablet for oral use.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Determine the safety of tovorafenib in combination with other therapies	Incidence and severity of adverse events	Up to 48 months
Phase 1b: Determine the MTD and RP2D of tovorafenib in combination with other therapies	Incidence and severity of adverse events	Up to 48 months
Phase 2: Evaluate the efficacy of tovorafenib monotherapy or in combination with other therapies	Overall response rate (ORR) as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	Up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Assess efficacy of tovorafenib in combination with other therapies	Duration of response (DOR) in patients with best overall response of CR or PR	Up to 48 months
Phase 1b & 2: Assess additional efficacy parameters of tovorafenib alone and in combination with other therapies	Duration of progression-free survival (PFS) and overall survival (OS)	Up to 48 months
Phase 1b & 2: Characterize tumor responses observed with tovorafenib alone and in combination with other therapies	Time to response (TTR) in patients with best overall response of CR or PR; and comparing the DOR in patients with CR or PR with the DOR observed with the immediate prior line of anticancer treatment	Up to 48 months
Phase 1b & 2: Characterize the pharmacokinetic (PK) profile of tovorafenib alone and in combination with other therapies	Measure plasma concentration of tovorafenib	Up to 48 months
Phase 1b & 2: Characterize the pharmacodynamic (PD) profile of tovorafenib alone and in combination with other therapies	Evaluate changes from baseline of phosphorylated ERK and other relevant biomarkers	Up to 48 months
Phase 2: Assess the safety and tolerability of tovorafenib as monotherapy, or in combination with other therapies	Incidence and severity of adverse events	Up to 48 months

Collaborators and Investigators

• Sponsor: Day One Biopharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2021
• Primary Completion (Estimated): July 31, 2025
• Study Completion (Estimated): December 31, 2025

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 (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: BRAF fusion; CRAF/RAF1 fusion; CRAF/RAF1 amplification
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Thyroid Diseases; Head and Neck Neoplasms; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Adenocarcinoma, Papillary; Thyroid Neoplasms; Skin Neoplasms; Carcinoma; Pancreatic Neoplasms; Melanoma; Astrocytoma; Thyroid Cancer, Papillary; Carcinoma, Acinar Cell; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Niacinamide
• Other Study ID Numbers: DAY101-102

Drug and device information, study documents

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