Melanoma, Solid Tumor, Pilocytic Astrocytoma, Non Small Cell Lung Cancer, Colorectal Cancer, Pancreatic Cancer, MAP Kinase Family Gene Mutation, RAS Mutation, RAF Mutation, MEK Mutation
Conditions
Keywords
DAY101, Mitogen-activated protein kinase, tovorafenib, pimasertib, DAY201
Brief summary
This is a subprotocol of Master Protocol DAY101-102 and is a Phase 1b/2, multi-center, open label subprotocol of participants ≥12 years of age, with recurrent or progressive solid tumors with alterations in the key proteins of the MAPK pathway, such as tumors that harbor RAS or RAF alterations. \*Note: Study concluded as Phase 1b only.
Interventions
DRUGTovorafenib
Tovorafenib tablet for oral use.
DRUGTovorafenib Drug: Pimasertib
Tovorafenib tablet for oral use. Pimasertib capsule for oral use
Sponsors
Day One Biopharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent by participant ≥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. * Participants must have a report of histologically confirmed diagnosis of tumor and a concurrent MAPK pathway alteration (genomic alterations in RAS, RAF, MEK, or NF1) 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 * Participants must have radiographically stable, recurrent or progressive disease that is measurable using the appropriate tumor response criteria eg, (RECIST version 1.1, RANO) * Archival tumor tissue should be preferably less than 3 years old. If unavailable, a freshly acquired tumor tissue biopsy or liquid biopsy is required * If brain metastases are present, they must have been previously treated and be stable as assessed by radiographic imaging
Exclusion criteria
* Known presence of concurrent activating alterations * Participants 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 * Participants who have an unstable neurological condition, despite adequate treatment (eg, uncontrolled seizures) * Participants with history of acute neurological events (such as intracranial or subarachnoid hemorrhage, stroke, intracranial trauma) within the past 6 months * History of second malignancy within 3 years prior to study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer, or superficial bladder cancer
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of participants who will report Treatment emergent adverse events (TEAEs) and serious TEAEs | Up to 30 days after the last dose of any study drug |
| Number of participants who will report clinically significant changes in vital signs | Up to 30 days after the last dose of any study drug |
| Number of participants who will report clinically significant changes in clinical chemistry parameters | Up to 30 days after the last dose of any study drug |
| Number of participants who will report clinically significant changes in hematology parameters | Up to 30 days after the last dose of any study drug |
| Number of participants with Dose limiting toxicities (DLTs) | Up to 30 days after the last dose of any study drug |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma concentration of DAY101 | Cycles 1 through Cycle 11 (each cycle is 28 days) | — |
| Maximum drug concentration (Cmax) of DAY101 | Cycle 1, Day 1 through Cycle 1, Day 22 | — |
| Percentage of participants with complete overall response rate (ORR) | Up to 30 months | ORR as assessed by the proportion of participants 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 |
| Change in gene expression levels in pre and post treatment samples using RNA sequencing (RNA seq) analysis. | Up to 30 months | — |
| Change in expression levels of phosphorylated ERK (pERK) and Ki67 in pre and post treatment samples using immunohistochemistry methodology. | Up to 30 months | — |
| Area Under the Curve from Time Zero to Last Measurable Concentration (AUC 0-last) | Cycle 1, Day 1 through Cycle 1, Day 22 | — |
| Duration of response (DOR) | Up to 30 months | The interval from the date of the first documentation of tumor response (CR or PR) that was subsequently confirmed by investigator assessment to the date of first occurrence of radiographic disease progression based on appropriate tumor response criteria as assessed by investigator or death due to any cause, whichever occurs earlier. |
| Progression Free Survival (PFS) | Up to 30 months | The interval from the date of the first dose to the first occurrence of radiographic disease progression based on appropriate tumor response criteria as assessed by investigator or death due to any cause, whichever occurs earlier. |
| Overall Survival (OS) | Up to 30 months | The interval from the date of the first dose until the recorded date of death due to any cause. |
| Time to Response | Up to 30 months | Defined in participants with best overall response of CR or PR as determined by Investigator, time to response is defined as the interval from the date of the first dose to date of first documentation of tumor response (CR or PR) that was subsequently confirmed by investigator assessment. |
Countries
Canada, United States
Outcome results
None listed