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About
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 FOLOX, 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.
Full description
PRIMARY OBJECTIVES:
I. To assess dose-limiting toxicities (DLTs) and determine the recommended phase 2 dose (RP2D) of CA-4948 (emavusertib) in combination with leucovorin (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab in first-line treatment for patients with advanced or metastatic non-operable colorectal cancer (mCRC).
II. To evaluate the safety and tolerability of the combination of CA-4948 (emavusertib) and FOLFOX plus bevacizumab.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To evaluate ribonucleic acid sequencing (RNAseq) data to examine the impact of IRAK4 inhibition on downstream signaling in tumor samples.
EXPLORATORY OBJECTIVES:
I. To evaluate pharmacodynamic (PD) effect of CA-4948 (emavusertib) in combination with chemotherapy.
II. To evaluate pharmacokinetics (PKs) of CA-4948 (emavusertib) in combination with chemotherapy.
III. To explore biomarkers and genomic alterations associated with treatment response.
IV. To evaluate if certain gene mutations alone or in combination are associated with response, progression free survival (PFS), and/or overall survival (OS).
OUTLINE: This is a dose-escalation study of CA-4948 in combination with FOLFOX plus bevacizumab followed by a dose-expansion study. Patients are assigned to 1 of 2 groups.
GROUP A: Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-14 of each cycle, bevacizumab intravenously (IV) over 30-90 minutes on day 1 of each cycle beginning in cycle 1, and oxaliplatin IV over 120 minutes, leucovorin calcium (leucovorin) IV over 2 hours, and fluorouracil IV bolus followed by continuous IV infusion over 46 hours on day 1 of each cycle. Cycles repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After treatment for 2 years, patients may continue treatment after discussion with the study chair. Patients also undergo blood sample collection and computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT throughout the trial. Patients may also undergo tumor biopsy throughout the trial.
GROUP B: Patients receive CA-4948 PO BID on days 1-14 of each cycle, bevacizumab IV over 30-90 minutes on day 1 of each cycle beginning in cycle 2, and oxaliplatin IV over 120 minutes, leucovorin IV over 2 hours, and fluorouracil IV bolus followed by continuous IV infusion over 46 hours on day 1 of each cycle. Cycles repeat every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After treatment for 2 years, patients may continue treatment after discussion with the study chair. Patients also undergo blood sample collection and CT, MRI, or PET/CT throughout the trial. Patients also undergo tumor biopsy throughout the trial.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 12 months after end of treatment.
Enrollment
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Inclusion criteria
Exclusion criteria
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) (> 470 in females, > 450 in males) 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
Patients who have received prior treatment with any chemotherapy (either in the adjuvant or metastatic setting), including FOLFOX, fluorouracil/leucovorin/irinotecan (FOLFIRI), folinic acid/fluorouracil/oxaliplatin/irinotecan (FOLFOXIRI), or antiangiogenic agents such as bevacizumab and similar agents, are not eligible for this study
Patients with a known dihydropyrimidine dehydrogenase deficiency
Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948 (emavusertib) or other agents used in the study
Patients with a gastrointestinal (GI) condition that could impair absorption of CA-4948 (emavusertib) or cause an inability to ingest CA-4948 (emavusertib)
Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
Pregnant women are excluded from this study because CA-4948 (emavusertib) is a blood-brain barrier penetrant with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CA-4948 (emavusertib), breastfeeding should be discontinued if the mother is treated with CA-4948 (emavusertib). These potential risks may also apply to other agents used in this study. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry
Patients with a history of allogeneic organ or stem cell transplantation
Patients with significant active bleeding or those in whom the treating physician believes bevacizumab would not be safe or appropriate
Patients who have had palliative radiation to bone metastases within 2 weeks prior to day 1 of the study treatment
Patients who have had a major surgical procedure within 4 weeks prior to day 1 of the study treatment
Patients with hypertension not controlled by antihypertensive medication
Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization; however,
Severe infections within 28 days prior to registration, including but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. This includes receipt of oral or IV antibiotics within 14 days prior to registration. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
Primary purpose
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Interventional model
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24 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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