Emavusertib + Chemotherapy for Colorectal Cancer

Recruiting at 18 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Antiangiogenics

Disqualifiers: MSI-H, dMMR, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 30

Duration: Up to 2 years

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and examine the side effects of a new drug, CA-4948 (Emavusertib), when combined with the standard chemotherapy treatment FOLFOX and bevacizumab for individuals with metastatic colorectal cancer. CA-4948 may inhibit cancer cell growth by blocking certain enzymes, while FOLFOX and bevacizumab work to prevent cancer cells from growing and spreading through different mechanisms. This trial may suit those diagnosed with colorectal cancer that is inoperable or has metastasized and who have not yet received chemotherapy for their metastatic cancer. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be on a stable dose of any cholesterol-lowering statin for at least 3 weeks before starting the study. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CA-4948, also known as Emavusertib, is generally safe when used alone in patients with certain blood cancers, such as acute myeloid leukemia (AML). In these studies, patients tolerated the drug well, and some even responded positively to the treatment.

Early results suggest that when combined with chemotherapy drugs like FOLFOX and the cancer drug bevacizumab, CA-4948 might be safe and tolerable for treating advanced colorectal cancer. This combination works by stopping tumor growth through blocking enzymes needed for cell growth and cutting off the tumor's blood supply.

This trial is in its early stages, focusing mainly on assessing safety and determining the right dose. The use of CA-4948 with established chemotherapy drugs like FOLFOX and bevacizumab, already used for colorectal cancer, offers some reassurance about the safety of the treatment plan. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for colorectal cancer?

Researchers are excited about Emavusertib because it offers a novel approach to treating colorectal cancer. Unlike standard treatments that primarily rely on chemotherapy drugs like FOLFOX, Emavusertib is an oral medication that targets IRAK4, a protein playing a key role in cancer cell survival and inflammation. This targeted mechanism of action could potentially enhance the effectiveness of existing chemotherapy by attacking the cancer from a different angle. By combining Emavusertib with standard chemotherapy and bevacizumab, the hope is to improve outcomes and possibly reduce side effects compared to chemotherapy alone.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal cancer?

Studies have shown that CA-4948, also known as Emavusertib, might help treat advanced colorectal cancer. This trial will evaluate CA-4948 combined with chemotherapy drugs like fluorouracil and oxaliplatin, and the drug bevacizumab. CA-4948 blocks certain proteins that tumors need to grow, potentially stopping cancer cells from spreading. Early findings suggest that, when used with these chemotherapy drugs, it could slow tumor growth. Although more research is needed, these initial results indicate potential benefits for patients with advanced colorectal cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Susanna V Ulahannan

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults over 18 with metastatic colorectal cancer, who are physically able to undergo treatment (ECOG ≤ 2), and have not had previous treatments that would exclude them. They must have a certain level of blood cells, liver function within set limits, and kidney function or filtration rate above a threshold. Tumors should be measurable by standard criteria and accessible for biopsy.

Inclusion Criteria

My total bilirubin levels are within the normal range.

My white blood cell count is healthy.

My platelet count is at least 75,000.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CA-4948 in combination with FOLFOX plus bevacizumab. Cycles repeat every 14 days for up to 2 years.

Up to 2 years

Bi-weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

12 months

Follow-up at 30 days and then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• CA-4948 (Emavusertib)

Trial Overview

The trial tests the safety and optimal dose of CA-4948 (Emavusertib) combined with FOLFOX chemotherapy plus Bevacizumab in patients with metastatic colorectal cancer. It aims to see if this combination can effectively stop tumor growth by blocking enzymes needed for cell growth and cutting off the tumor's blood supply.

How Is the Trial Designed?

Group I: Group B (CA-4948, bevacizumab, FOLFOX) Experimental Treatment 10 Interventions

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.

Group II: Group A (CA-4948, bevacizumab, FOLFOX) Experimental Treatment 10 Interventions

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 1, 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 may also undergo tumor biopsy throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 43 patients with metastatic colorectal cancer (mCRC) who were resistant to standard treatments, TAS-102 provided clinically relevant disease control in 30% of patients, particularly those treated for 6 or more cycles, with a median progression-free survival of 7.5 months and overall survival of 11.2 months.

A significant correlation was found between previous treatment success with regorafenib and the efficacy of TAS-102, suggesting that patients who responded well to regorafenib may benefit more from subsequent treatment with TAS-102.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome of patients with chemorefractory metastatic colorectal cancer treated with trifluridine/tipiracil (TAS-102): a single Italian institution compassionate use programme. Sforza, V., Martinelli, E., Cardone, C., et al.[2021]

In a phase II study involving 48 patients with unresectable or metastatic colorectal cancer, an alternating regimen of mFOLFOX6 and FOLFIRI resulted in a promising overall response rate of 58.7% and a median overall survival of 28.4 months.

The treatment was well tolerated, with a low incidence of severe neurotoxicity (0%) and manageable adverse events, indicating a favorable safety profile for this chemotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701). Oki, E., Emi, Y., Akagi, Y., et al.[2014]

Oral uracil-tegafur (UFT) plus leucovorin (LV) and infusional fluorouracil (5-FU) plus LV show similar overall survival and tumor response rates in advanced colorectal cancer, based on pooled data from five randomized controlled trials.

However, the oral UFT regimen has significantly lower rates of severe toxicities, such as leucopenia and infections, making it a safer option for patients compared to the 5-FU regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral uracil-tegafur plus leucovorin vs fluorouracil bolus plus leucovorin for advanced colorectal cancer: a meta-analysis of five randomized controlled trials. Bin, Q., Li, J., Liao, C., et al.[2019]

In a phase II trial involving 44 patients with metastatic colorectal carcinoma, a regimen of weekly oxaliplatin, high-dose infusional 5-FU, and leucovorin showed a favorable tolerability profile with no grade IV toxicity observed, although common side effects included gastrointestinal issues and neurotoxicity.

The treatment resulted in a 23% partial response rate and a median overall survival of 13 months, indicating that this combination therapy is effective and warrants further investigation in larger phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of weekly oxaliplatin and high-dose infusional 5-fluorouracil plus leucovorin in pretreated patients with metastatic colorectal cancer. Chiara, S., Nobile, MT., Gozza, A., et al.[2018]

Regorafenib is an effective oral multikinase inhibitor used in treating colorectal cancer, targeting multiple pathways involved in tumor growth.

Aflibercept and ramucirumab are both angiogenesis inhibitors that help treat metastatic colorectal cancer by blocking blood vessel formation, with aflibercept being the second FDA-approved anti-angiogenic agent for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New molecular targeting drugs for metastatic colorectal cancer]. Komatsu, Y., Harada, K., Fukushima, H., et al.[2023]

In a study of 213 patients with metastatic colorectal cancer, the addition of bevacizumab (BV) to the FOLFOX4 regimen significantly improved median progression-free survival (PFS) from 9.9 months to 17.0 months and overall survival (OS) from 20.5 months to 38.8 months.

The results suggest that adding BV to FOLFOX4 provides substantial survival benefits, and maintenance therapy with 5-fluorouracil plus leucovorin during oxaliplatin suspension may further enhance survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective analysis on the efficacy of bevacizumab with FOLFOX as a first-line treatment in Japanese patients with metastatic colorectal cancer. Suenaga, M., Mizunuma, N., Matsusaka, S., et al.[2015]

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Clinical trial of an anti-cancer drug, CA-4948 (Emavusertib), in combination with chemotherapy treatment (FOLFOX Plus Bevacizumab) in metastatic colorectal ...