Clinical trial NCT06346067: A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2)
Official title: A Randomized, Open-label Phase III Study in Patients With Previously Treated Unresectable or Metastatic NRAS Mutant Cutaneous Melanoma Comparing the Combination of Naporafenib + Trametinib to Physician's Choice of Therapy (Dacarbazine, Temozolomide or Trametinib Monotherapy) With a Dose Optimization lead-in [SEACRAFT-2]
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Advanced or Metastatic NRAS-mutant Melanoma
Keywords: Melanoma
NRAS Mutant
Cutaneous Melanoma
Lead sponsor: Erasca, Inc.
Sponsor class: INDUSTRY
First posted: 2024-04-03
Enrollment: 470
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Stage 1: To select the optimal dose of naporafenib + trametinib to be studied in Stage 2.

Stage 2: To compare progression free survival (PFS) and overall survival (OS) for patients with NRAS-mutant (NRASm) melanoma who are randomized to receive the combination of naporafenib + trametinib to that of patients who are randomized to physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy).

Detailed description: SEACRAFT-2 is a global, Phase III, open-label, randomized study to assess the efficacy and safety of naporafenib administered with trametinib compared to physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy) in patients with unresectable or metastatic NRAS mutant melanoma who have progressed on, or are intolerant to, an anti-programmed death-1 ligand 1 (PD 1/L1)-based regimen. The study will consist of 2 stages: dose optimization in Stage 1 and the Phase 3 portion in Stage 2.

A total of approximately 470 eligible patients will be randomized to receive study drug(s) in this study across 2 stages.

Eligibility criteria: Key Inclusion Criteria:

1. Willing and able to provide written informed consent
2. Age ≥ 18 years
3. Histologically or cytologically confirmed unresectable or metastatic cutaneous (includes acral) melanoma.
4. Documentation of an NRAS mutation (tumor tissue or blood) prior to first dose of study drug(s) as determined locally with an analytically validated assay in a certified testing laboratory.
5. Archival tumor tissue collected within 5 years prior to enrollment must be confirmed to be available at the time of Screening, which may be submitted before or after enrollment for exploratory biomarker analysis.
6. Must have received an anti-PD-1/L1 based regimen (monotherapy or combination). Patient must have documented disease progression either while receiving therapy or within 12 weeks of last dose of the most recent anti-PD-1/L1 based regimen; the patient is eligible if they have received other therapies between the most recent anti-PD-1/L1 based regimen and enrollment.
7. ECOG performance status 0, 1 or 2
8. Presence of at least 1 measurable lesion according to RECIST v1.1
9. Able to swallow oral medication.

Key Exclusion Criteria:

1. Patients with uveal or mucosal melanoma
2. Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor
3. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug(s) (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndrome)
5. LVEF \<50%
6. Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
7. Patients receiving treatment with herbal medicine known to cause liver toxicity, which cannot be discontinued 7 days prior to first dose of study drug(s) and for the duration of the study.
8. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

Primary outcomes:
measure: Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2
timeFrame: Assessed up to 6 months from time of first dose
measure: Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2
timeFrame: Assessed up to 6 months from time of first dose
measure: Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2
timeFrame: Study Day 1 up to Day 29
measure: Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2
timeFrame: Study Day 1 up to Day 29
measure: Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2
timeFrame: Study Day 1 up to Day 29
measure: Stage 2: To compare PFS and OS for patients who are randomized to receive the combination of naporafenib + trametinib to that of patients who receive physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy)
timeFrame: Assessed up to 24 months from time of first dose
Secondary outcomes:
measure: Adverse Events
timeFrame: Assessed up to 24 months from time of first dose
measure: Duration of Response (DOR)
timeFrame: Assessed up to 24 months from time of first dose]
measure: Time to Response (TTR)
timeFrame: Assessed up to 24 months from time of first dose]
measure: Disease Control Rate (DCR)
timeFrame: Assessed up to 24 months from time of first dose]
measure: Overall Response Rate (ORR)
timeFrame: Assessed up to 24 months from time of first dose
measure: Plasma concentration (Cmax):Stage 1 only
timeFrame: Study Day 1 up to Day 29
measure: Area under the curve (AUC):Stage 1 only
timeFrame: Study Day 1 up to Day 29
measure: Quality of Life: To assess disease and treatment-related QOL in patients with NRASm melanoma.
timeFrame: Assessed up to 24 months from time of first dose
Other outcomes:
measure: Duration of Response (DOR) for CNS disease in participants
timeFrame: Assessed up to 24 months from time of first dose
measure: Overall Response Rate (ORR) for CNS disease in participants
timeFrame: Assessed up to 24 months from time of first dose
measure: Disease Control Rate (DCR) for CNS disease in participants
timeFrame: Assessed up to 24 months from time of first dose
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Englewood
country: United States
facility: The Melanoma and Skin Care Institute
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic - Florida
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Cancer
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Jefferson
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Nashville
country: United States
facility: SCRI Oncology Partners (formerly Tennessee Oncology)
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology- Austin Midtown
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: The University of Utah - Huntsman Cancer Institute (HCI)
state: Utah
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Southport
country: Australia
facility: Tasman Health Care
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Institute
state: Victoria
city: Nedlands
country: Australia
facility: Hollywood Private Hospital
state: Western Australia
city: Melbourne
country: Australia
facility: Alfred Hospital
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Brno
country: Czechia
facility: Masarykuv Onkologicky Ustav-MOU
city: Nový Hradec Králové
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Prague
country: Czechia
facility: Sanatorium Profesora Arenbergera
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire (CHU) de Bordeaux - Hospitalier Saint-Andre
city: Dijon
country: France
facility: CHU Dijon Bourgogne - Hopital Francois Mitterand (Hopital du Bocage)
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Lille
country: France
facility: CHRU de Lille - HÃ´pital Claude Huriez
city: Lyon
country: France
facility: Centre Hospitalier Lyon-Sud
city: Marseille
country: France
facility: Assistance Publique Hopitaux de Marseille (AP-HM) - Hopital de la Timone
city: Paris
country: France
facility: Hospital Ambroise Pairs
city: Paris
country: France
facility: APHP - Hopital Saint Louis
city: Villejuif
country: France
facility: CLCC Institute Gustave Roussy
city: Milan
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele (HSR) (Istituto Scientifico Universitario Sa
city: Roma
country: Italy
facility: IRCCS Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: Istituto Dermopatico dell Immacolata IDI-IRCCS
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria del Friuli Centrale
city: Amsterdam
country: Netherlands
facility: Isala Ziekenhuis
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Nijmegen
country: Netherlands
facility: Radboud University
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron - Vall d'Hebron Institut d'Oncologia (VHIO)
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital HM Sanchinarro
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
state: Lancashire
city: City of London
country: United Kingdom
facility: Sarah Cannon Research Institute - HCA Healthcare
state: London
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Christie Hospital
Study officials:
affiliation: Clinical Development
name: Joyce Antal
role: STUDY_DIRECTOR
References: