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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04985604
• Other study ID #: DAY101-102
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: July 15, 2021
• Est. completion date: December 31, 2025

Study information

• Verified date: March 2024
• Source: Day One Biopharmaceuticals, Inc.
• Contact: Day One Biopharmaceuticals
• Phone: 650-484-0899
• Email: clinicaltrials[@]dayonebio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 168
• Est. completion date: December 31, 2025
• Est. primary completion date: July 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Astrocytoma
• Bladder Cancer
• Bladder Urothelial Carcinoma
• Carcinoma
• Colorectal Cancer
• MEK Mutation
• Melanoma
• Non Small Cell Lung Cancer
• Non-Small Cell Adenocarcinoma
• Pancreatic Acinar Carcinoma
• Pancreatic Neoplasms
• Pilocytic Astrocytoma
• RAS Mutation
• Solid Tumor
• Thyroid Cancer, Papillary

Intervention

Drug:
• Tovorafenib
Tovorafenib tablet for oral use.
• Pimasertib
Pimasertib capsule for oral use.

Locations

Country	Name	City	State
Australia	Monash Medical Centre	Clayton	Victoria
Belgium	Antwerp University Hospital	Edegem
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	The Hospital for Sick Children	Toronto	Ontario
France	Hopital de La Timone - APHM	Marseille	Bouches-du-Rhône
Korea, Republic of	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
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Ramón y Cajal	Madrid
United States	University of Colorado Hospital	Aurora	Colorado
United States	Community North Cancer Center	Indianapolis	Indiana
United States	Cancer Specialists of North Florida	Jacksonville	Florida
United States	The Angeles Clinic	Los Angeles	California
United States	Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Hoag Health	Newport Beach	California
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	OHSU Knight Cancer Institute	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Day One Biopharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Korea, Republic of,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1b: Determine the safety of tovorafenib in combination with other therapies	Incidence and severity of adverse events	Up to 48 months
Primary	Phase 1b: Determine the MTD and RP2D of tovorafenib in combination with other therapies	Incidence and severity of adverse events	Up to 48 months
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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