Clinical trial NCT04985604: Tovorafenib (DAY101) Monotherapy or in Combination With Other Therapies for Patients With Melanoma and Other Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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
Keywords: BRAF fusion
CRAF/RAF1 fusion
CRAF/RAF1 amplification
Lead sponsor: Day One Biopharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-02
Enrollment: 168
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 1b: Determine the safety of tovorafenib in combination with other therapies
timeFrame: Up to 48 months
measure: Phase 1b: Determine the MTD and RP2D of tovorafenib in combination with other therapies
timeFrame: Up to 48 months
measure: Phase 2: Evaluate the efficacy of tovorafenib monotherapy or in combination with other therapies
timeFrame: Up to 48 months
Secondary outcomes:
measure: Phase 1b: Assess efficacy of tovorafenib in combination with other therapies
timeFrame: Up to 48 months
measure: Phase 1b & 2: Assess additional efficacy parameters of tovorafenib alone and in combination with other therapies
timeFrame: Up to 48 months
measure: Phase 1b & 2: Characterize tumor responses observed with tovorafenib alone and in combination with other therapies
timeFrame: Up to 48 months
measure: Phase 1b & 2: Characterize the pharmacokinetic (PK) profile of tovorafenib alone and in combination with other therapies
timeFrame: Up to 48 months
measure: Phase 1b & 2: Characterize the pharmacodynamic (PD) profile of tovorafenib alone and in combination with other therapies
timeFrame: Up to 48 months
measure: Phase 2: Assess the safety and tolerability of tovorafenib as monotherapy, or in combination with other therapies
timeFrame: Up to 48 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic
state: California
city: Newport Beach
country: United States
facility: Hoag Health
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Indianapolis
country: United States
facility: Community North Cancer Center
state: Indiana
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Marseille
country: France
facility: Hopital de La Timone - APHM
state: Bouches-du-Rhône
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
Study officials:
References: