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

Phase 1

Recruiting

• Conditions: Melanoma; Solid Tumor; CRAF Gene Amplification; Spitzoid Melanoma; Pilocytic Astrocytoma; Pilocytic Astrocytoma, Adult; Non Small Cell Lung Cancer; Non-Small Cell Adenocarcinoma; Colorectal Cancer; Pancreatic Acinar Carcinoma
• Interventions: Drug: Tovorafenib; Drug: Pimasertib

• Registration Number: NCT04985604
• Lead Sponsor: Day One Biopharmaceuticals, Inc.

Brief Summary

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.

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 Timeline

• Study First Submitted: 2021-06-23
• Study Start: 2021-07-15
• Study First Submitted QC: 2021-07-30
• Study First Posted: 2021-08-02
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-27
• Last Update Posted: 2024-03-29
• Primary Completion: 2025-07-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 168

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm #1 (Closed to Enrollment)	Tovorafenib	Tovorafenib monotherapy
Arm #2	Tovorafenib	Tovorafenib plus pimasertib
Arm #2	Pimasertib	Tovorafenib plus pimasertib

Primary Outcome Measures

Name	Time	Method
Phase 1b: Determine the safety of tovorafenib in combination with other therapies	Up to 48 months	Incidence and severity of adverse events
Phase 2: Evaluate the efficacy of tovorafenib monotherapy or in combination with other therapies	Up to 48 months	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
Phase 1b: Determine the MTD and RP2D of tovorafenib in combination with other therapies	Up to 48 months	Incidence and severity of adverse events

Secondary Outcome Measures

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

Trial Locations

Locations (20)

The Angeles Clinic; 🇺🇸 Los Angeles, California, United States

Hoag Health; 🇺🇸 Newport Beach, California, United States

University of Colorado Hospital; 🇺🇸 Aurora, Colorado, United States

Cancer Specialists of North Florida; 🇺🇸 Jacksonville, Florida, United States

Community North Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

OHSU Knight Cancer Institute; 🇺🇸 Portland, Oregon, United States

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

Vanderbilt-Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Monash Medical Centre; 🇦🇺 Clayton, Victoria, Australia

Antwerp University Hospital; 🇧🇪 Edegem, Belgium

Princess Margaret Cancer Centre; 🇨🇦 Toronto, Ontario, Canada

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

Hopital de La Timone - APHM; 🇫🇷 Marseille, Bouches-du-Rhône, France

Dong-A University Hospital; 🇰🇷 Busan, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

Hospital Clinic Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Universitario Ramón y Cajal; 🇪🇸 Madrid, Spain