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

Day One Biopharmaceuticals

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: CRAF Gene Fusion; Solid Tumor; Melanoma; CRAF Gene Amplification; Bladder Urothelial Carcinoma; Non Small Cell Lung Cancer; Pilocytic Astrocytoma, Adult; Bladder Cancer; RAF1 Gene Amplification; RAF Mutation; RAF1 Gene Fusion; MEK Mutation; BRAF Fusion; Thyroid Cancer, Papillary; Non-Small Cell Adenocarcinoma; CRAF Fusion; RAF1 Fusion; Pilocytic Astrocytoma; MAP Kinase Family Gene Mutation; Spitzoid Melanoma; BRAF Gene Fusion; Spitzoid Malignant Melanoma; RAS Mutation; Pancreatic Acinar Carcinoma; Colorectal Cancer

Treatments: Drug: Tovorafenib; Drug: Pimasertib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04985604

DAY101-102

Details and patient eligibility

About

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.

Full 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.

Enrollment: 168 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

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

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)

Substudy A-specific exclusion criterion:

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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168 participants in 2 patient groups

Arm #1 (Closed to Enrollment)

Experimental group

Description:

Tovorafenib monotherapy

Treatment:

Drug: Tovorafenib

Arm #2

Experimental group

Description:

Tovorafenib plus pimasertib

Treatment:

Drug: Pimasertib

Drug: Tovorafenib