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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: Tovorafenib
* Drug: Pimasertib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm #1<br>Tovorafenib monotherapy | Drug: Tovorafenib<br>* Tovorafenib tablet for oral use.<br>|
| Experimental: Arm #2<br>Tovorafenib plus pimasertib | Drug: Tovorafenib<br>* Tovorafenib tablet for oral use.<br>Drug: Pimasertib<br>* Pimasertib capsule for oral use.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRAF fusion, CRAF/RAF1 fusion, CRAF/RAF1 amplification