Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations
Conditions
Interventions
Product Name: DAY101
Pharmaceutical Form: Tablet
INN or Proposed INN: tovorafenib
CAS Number: 1096708-71-2
Current Sponsor code: DAY101
Other descriptive name: MLN2480, TAK-580, BSK1369, BIIB024
Conce
Sponsors
Day One Biopharmaceuticals, Inc. (Day One)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Master Protocol: Eligibility criteria can be found within each sub-protocol. Sub study : 1. Signed informed consent by patients = 12 years of age; either a Consent or an Assent Form will be provided to the patient based on their capacity, local regulations, and guidelines. 2. Patients must have a report of histologically confirmed diagnosis of melanoma or other solid tumor and a BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplifications obtained 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 regulatory agency 3. Patients must have radiographically documented recurrent or radiographically documented progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1, RANO). Imaging must be performed within 28 days prior to the first dose of study drug . 4. Patients must have progressed after and are not suitable for standard of-care treatment, including locally directed therapy, such as surgery or radiotherapy, prior to documented radiographic progression. 5. Archival tumor tissue should be preferably less than 3 years old. If unavailable, a freshly acquired tumor tissue or liquid biopsy obtained at baseline to confirm presence of MAPK alteration is required. 6. Previous chemotherapy and hormone therapy (excluding physiologic replacement) must be completed at least 4 weeks or 5 half-lives, whichever occurs first, prior to initiation of therapy. 7. Previous immunotherapy/monoclonal antibody/targeted therapy use must be completed at least 2 weeks or 5 half-lives (whichever is shorter) prior to initiation of therapy. In addition, radiation therapy to the target lesion must be completed at least 6 months prior to initiation of therapy. 8. All associated toxicity from previous therapies must be resolved to = Grade 1 or considered baseline prior to initiation of therapy. 9. If brain metastases are present, they must have been previously treated and be stable by radiographic imaging (must have imaging taken = 4 weeks from treatment of brain metastasis) AND, if receiving corticosteroids, the patient must be neurologically stable by clinical examination and on a stable or a decreasing dose of corticosteroids within 7 days prior to study start. 10. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1; For patients 70. 11. Acceptable end-organ function as demonstrated by the following laboratory values 12. Thyroid function tests must be consistent with stable thyroid function. Patients must be on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting study drug. 13. Left ventricular ejection fraction (LVEF) = 50% or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) within 28 days before the first dose of study drug. 14. Ability to comply with outpatient treatment, laboratory monitoring, required clinic visits, and required imaging studies for the duration of study participation. 15. Willingness of male and female patients with reproductive potential to use double highly effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Highly effective birth control methods ar
Exclusion criteria
Exclusion criteria: Master Protocol: Eligibility criteria can be found within each sub-protocol. Sub study Protocol A: 1. Prior receipt of any RAS-, RAF-, MEK-, or ERK-directed inhibitor therapy. 2. Known presence of concurrent activating alterations. Examples include, but are not limited, to the following: EGFR, ALK, MET, ROS, FGFR, RET, NTRK, PIK3CA, IDH1/2, and cKIT. Genomic profile of tumor under study will be reviewed by the Sponsor to confirm eligibility. 3. Current enrollment in any other investigational treatment study. 4. Patients with current evidence or a history of serous retinopathy (SR), retinal vein occlusion (RVO), or ophthalmopathy present at screening or baseline who would be considered at risk for SR or RVO. 5. Patients who have an unstable neurological condition, despite adequate treatment (e.g., uncontrolled seizures). 6. Evidence of current uncontrolled cardiovascular conditions, including but not limited to clinically significant cardiac arrythmias (such as ventricular arrhythmias, atrial fibrillation or recent recovery of rhythm after atrial fibrillation, bradycardia), congestive heart failure, angina, ischemia or myocardial infarction ventricular hypertrophy, cardiomyopathy, conduction disorder, or cerebrovascular accident (CVA), within the past 6 months. see protocol Sub protocol B 1. Prior receipt of any Type-II pan-RAF inhibitor therapy (e.g., LXH254/naporafenib, BGB-283, BGB-3245, belvarafenib). 2. Concomitant medications that are strong inhibitors or inducers of CYP2C8 and CYP2C19 within 14 days before initiation of therapy. Concomitant medications that are substrates of breast cancer resistance protein (BCRP) with a narrow therapeutic index within 14 days before initiation of therapy. 3. Known presence of concurrent activating alterations. Examples include, but are not limited, to the following: EGFR, ALK, MET, ROS, RET, FGFR, NTRK, PIK3CA, IDH1/2, and cKIT. Genetic profile of tumor under study, will be reviewed by the Sponsor to confirm eligibility. 4. Current enrollment in any other investigational treatment study. see protocol
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1b The Phase 1b objectives will apply to the investigation of DAY101 in combination with other therapies. Additional objectives may be specified according to the related sub-study protocol. Primary Objective: • To determine the safety of DAY101 in combination with other therapies. • To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of DAY101 in combination with other therapies. Phase 2 The Phase 2 objectives will apply to the investigation of DAY101 as monotherapy and in combination with other therapies. Additional objectives may be specified according to the relevant sub-study protocol. Primary Objective: To evaluate the efficacy of DAY101 by RECIST version 1.1 or appropriate tumor response criteria as a monotherapy or in combination with other therapies;Secondary Objective: Phase 1b: To assess the efficacy of DAY101 in combination with other therapies by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 To characterize the pharmacokinetic (PK) profile of DAY101 in combination with other therapies To characterize pharmacodynamic (PD) effects of DAY101 in combination with other therapies Phase 2: •To assess the safety and tolerability of DAY101 as monotherapy or in combination with othertherapies. •To assess additional efficacy parameters of DAY101 as monotherapy or in combination with othertherapies. •To characterize the tumor responses observed with DAY101 as monotherapy or in combination withother targeted therapies. •To characterize the PK profile of DAY101 in combination with other therapies, according to therelevant sub-study protocol. •To characterize the PD effects of DAY101 as monotherapy or in combination with other therapies. •To determine the relationship between PK and PD of DAY101 in combination with other therapies.;Primary end point(s): Phase 1b: • Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b: • ORR as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or partial response (PR) according to the appropriate tumor response criteria as assessed by Investigator • Duration of response (DOR) in patients with best overall response of CR or PR as determined by the treating Investigator [from time of first tumor response to progression or date of data analysis, whichever occurs earlier] • Duration of progression-free survival (PFS) following initiation of study treatment to disease progression, death, or date of analysis, whichever occurs earlier • Duration of overall survival (OS) following initiation of study treatment to time of death • Time to response (TTR) in patients with best overall response of CR or PR as determined by treating Investigator [from initiation of study treatment to date of first response] • Comparing the DOR in patients with CR or PR as determine by treating Investigator with the DOR observed with the immediate prior line of anticancer treatment • Plasma concentration of DAY101 at specified time points in order to define PK parameters • Measured by downstream MAPK pathway signaling, including pERK and other relevant pathway signaling using appropriate assay(s) on tumor biopsies obtained at baseline and on Cycle 1 Day 1 and Cycle 2 Day 1 (± 3 days) Phase2: • Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5 • Change from baseline in targeted vital signs • Change from baseline in targeted clinical laboratory test result • ORR as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or PR according to the appropriate tumor response criteria as assessed by Investigator • DOR in patients with best overall response of CR or PR as determined by the treating Investigator [from time of first tumor response to progression or date of data analysis, whichever occurs earl | — |
Countries
Australia, Belgium, Canada, France, Korea, Republic of, Spain, United States
Outcome results
None listed