This phase I trial studies the side effects and best dose of CA-4948 when given together with fluorouracil, leucovorin, oxaliplatin (FOLFOX) plus bevacizumab in treating patients with colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic). CA-4948 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The chemotherapy drugs used in FOLFOX, fluorouracil and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Leucovorin is used with fluorouracil to treat colorectal cancer. Bevacizumab is in a class of medications called anti-angiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to the tumor. This may slow the growth and spread of the tumor. Giving CA-4948 with FOLFOX plus bevacizumab may be safe, tolerable and/or effective in treating patients with metastatic colorectal cancer.
Patients must have histologically or cytologically confirmed colorectal adenocarcinoma
Patients must have unresectable or metastatic measurable disease on imaging for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 determination within 28 days of registration
For patients enrolling to the expansion cohort, lesions must be amenable to research biopsy
Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of CA-4948 (emavusertib) and FOLFOX in combination with bevacizumab in patients < 18 years of age, children are excluded from this study
Patients with high-frequency microsatellite instability (MSI-H) or deficient deoxyribonucleic acid (DNA) mismatch repair (dMMR) colorectal cancer at pre-enrollment screening
Patients with prolonged QT interval by Fridericia's correction formula (QTcF) (> 450ms) on screening electrocardiogram (ECG)
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), with the exception of alopecia
Patients who are receiving any other investigational agents
Sequential
Bevacizumab
Biological/VaccineGiven IV
Biopsy Procedure
Procedure/SurgeryUndergo tumor biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT or PET/CT
Emavusertib
Biological/VaccineGiven PO
Fluorouracil
DrugGiven IV
Leucovorin Calcium
DrugGiven IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Oxaliplatin
DrugGiven IV
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Dose limiting toxicities (DLT)
DLT will be based on the first 2 cycles (28 days) of emavusertib.
Incidence of treatment-emergent adverse events
The adverse events will be recorded by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Incidence of adverse events
Adverse events, graded according to the National Cancer Institute CTCAE v5 for each cohort, will be analyzed using descriptive statistics.
Overall response rate
Defined as the percentage of patients who achieve complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
Progression free survival
Will be assessed using RECIST v1.1.
Overall survival
Pharmacodynamic (PD) biomarkers
PD biomarkers including p-IRAK4, p-p65, p-ERK by immunohistochemistry (IHC) to determine the effect of IRAK4 inhibition by emavusertib before and after treatment will be analyzed using two-way analysis of variation (ANOVA) followed by post-doc pairwise comparison test.
Pharmacokinetic (PK) parameters
Emavusertib steady-state PK parameters will be estimated, specifically maximum concentration, area under the concentration-time curve, and apparent clearance using non-compartmental methods. PK parameters will be reported descriptively for exploratory comparison with historical data. Advanced population PK methods may be employed at a later stage to assess the link between drug exposure and biological effects and efficacy.
Immune profiling
Multiplex IHC will be used to assess T cell infiltrates, activation, and exhaustion, as well as myeloid and dendritic cell panels before and after treatment. This will be analyzed using a Wilcoxon signed-rank test.
Systemic immunity in circulation
This analysis will be performed using blood samples collected on the same day (+/- 3 days) as tumor biopsy. Will employ a 36-parameter cytometry by time-of-flight panel designed for adaptive and innate immune cells. Changes in each marker before and after treatment will be analyzed using two-way ANOVA followed by post-hoc pairwise comparison test.
Click on the lead sponsor to view all of their trials.
