ZEN003694 + Chemotherapy for Colorectal Cancer

Recruiting at 12 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Encorafenib, Cetuximab

Must not be taking: CYP3A4 inhibitors, Proton pump inhibitors

Disqualifiers: Uncontrolled illness, Allergic reactions, others

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

Compensation: Varies

Number of Visits: 5

Duration: 28-day cycles, repeated

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new drug, ZEN003694, combined with two existing treatments, cetuximab (a monoclonal antibody) and encorafenib (a BRAF inhibitor), for individuals with metastatic colorectal cancer unresponsive to other treatments. ZEN003694 targets and disrupts certain proteins to halt cancer cell growth, potentially enhancing the effectiveness of existing treatments. Suitable candidates have colorectal cancer that has spread and have tried at least one other treatment without success. Participants should also have a specific gene mutation called BRAF V600E and have previously tried cetuximab and encorafenib. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that are strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows at least 7 days before starting the study drug ZEN003694. If you are taking proton pump inhibitors, you will need to stop them as well. For H2 blockers or other acid-reducing agents, a specific dosing schedule must be followed.

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

Research has shown that ZEN003694 has been tested in over 550 patients and appears safe for long-term use. However, detailed information about side effects or the optimal dosage from these tests remains unavailable.

The other treatments in this trial, cetuximab and encorafenib, have been used in cancer treatment before. Studies have found that cetuximab, when combined with chemotherapy, can extend the lives of some people with certain types of colorectal cancer. Encorafenib has also proven safe and effective when used with other treatments, like chemotherapy, for some cancer patients.

While ZEN003694 is newer and still under study, cetuximab and encorafenib have a proven track record of safe use in cancer care. This trial aims to determine the best way to use these drugs together safely. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for colorectal cancer, which generally involve conventional chemotherapy and targeted therapies like cetuximab, this new combination therapy includes ZEN003694, a novel BET inhibitor. Researchers are excited about ZEN003694 because it targets specific proteins that regulate gene expression, potentially disrupting cancer cell growth more effectively than current options. Additionally, combining ZEN003694 with encorafenib, a BRAF inhibitor, could enhance the treatment's ability to target cancer cells with certain genetic mutations, offering a more personalized approach. This innovative combination may provide a new avenue for patients who have limited success with existing therapies.

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

In this trial, participants will receive a combination of ZEN003694, cetuximab, and encorafenib. Research has shown that cetuximab, when combined with chemotherapy, can significantly benefit patients with metastatic colorectal cancer. One study found that patients lived longer when they received cetuximab, with a hazard ratio of 0.87, indicating a noticeable improvement in survival compared to those who did not receive it. Encorafenib, another treatment in this trial, lowered the risk of death by 51% in patients with certain gene mutations. While researchers continue to study ZEN003694, it works by interfering with genes that help cancer cells grow, potentially stopping tumor growth. Together, these treatments could offer a promising option for those whose cancer hasn't responded to previous treatments. ^{4 6 7 8 9}

Who Is on the Research Team?

Salvador Alonso Martinez

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults over 18 with metastatic colorectal adenocarcinoma that's resistant to treatment and has a specific mutation (BRAF V600E). Participants need functioning liver and kidneys, an acceptable blood cell count, and if HIV-positive, must be on effective therapy with undetectable viral load.

Inclusion Criteria

I have another cancer type, but it won't affect this trial's treatment.

My doctor does not believe I need immediate treatment for my brain metastases.

My heart is healthy enough for treatment, according to NYHA class II or better.

Exclusion Criteria

I have recovered from side effects of previous cancer treatments, except for hair loss.

Patients who are receiving any other investigational agents

History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or other agents used in study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive ZEN003694 orally once daily, cetuximab intravenously on days 1 and 15, and encorafenib orally once daily in 28-day cycles

28-day cycles, repeated

2 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 2 months

Follow-up visits every 2 months

Dose Escalation

Determination of maximum tolerated dose and recommended phase 2 dose based on adverse events

Up to completion of dose escalation phase

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Encorafenib
• ZEN003694

Trial Overview The trial tests ZEN003694 combined with usual chemotherapy drugs cetuximab and encorafenib. It aims to find the safest dose of ZEN003694, see how well it works in treating refractory metastatic colorectal cancer compared to standard treatments alone.

How Is the Trial Designed?

Group I: Treatment (ZEN003694, cetuximab, encorafenib) Experimental Treatment 9 Interventions

Patients receive ZEN003694 PO QD on days 1-28 of each cycle, cetuximab IV over 120 minutes on days 1 and 15 of each cycle, and encorafenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, CT or MRI, and collection of blood samples throughout the trial. Patients may also undergo biopsy at screening and on study.

Cetuximab is already approved in United States, European Union for the following indications:

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

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 involving 65 patients with advanced colorectal cancer who had previously been treated with multiple therapies, the combination of cetuximab and irinotecan showed a response rate of 20% and a median overall survival of 10.4 months, confirming the efficacy of this treatment regimen.

The treatment was associated with low rates of severe toxicity, with only 8% experiencing grade 3 skin toxicity, indicating that cetuximab and irinotecan can be a safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Pfeiffer, P., Nielsen, D., Yilmaz, M., et al.[2018]

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth-factor receptor (EGFR) and has been clinically approved in Europe for treating metastatic colorectal cancer and locally advanced head and neck cancer since 2004 and 2006, respectively.

The review discusses cetuximab's established role in colorectal cancer treatment, ongoing studies, and future challenges, highlighting its significance as the leading anti-EGFR monoclonal antibody in clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: appraisal of a novel drug against colorectal cancer. Hildebrandt, B., le Coutre, P., Nicolaou, A., et al.[2019]

Cetuximab, a monoclonal antibody targeting the EGFR, has been approved for first-line treatment of KRAS mutation-negative metastatic colorectal cancer (mCRC) in combination with FOLFIRI, showing significant improvements in progression-free survival and overall survival.

The combination of cetuximab with FOLFIRI also resulted in higher objective response rates compared to FOLFIRI alone, making it a valuable treatment option for patients with EGFR-expressing, KRAS wild-type mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Lyseng-Williamson, KA.[2021]

Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and show promise as therapies for colorectal cancer, particularly in cases where chemotherapy has failed.

The review discusses their effectiveness in both advanced and initial treatment settings, as well as factors that may predict patient response or resistance to these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. Burtness, B.[2018]

In a study of 8 patients with recurrent/advanced colorectal cancer, 6 patients showed a positive response to cetuximab, a targeted therapy that binds to epidermal growth factor receptors (EGFR), indicating its efficacy even in later lines of treatment.

Patients receiving cetuximab in combination with CPT-11 had significantly better progression-free survival (7.3 months) and time to treatment failure (9.3 months) compared to those on cetuximab monotherapy (3.0 months and 4.5 months, respectively), highlighting the potential benefits of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. Katsumoto, Y., Aritake, N., Endoh, A.[2018]

Encorafenib in combination with cetuximab significantly improves overall survival (9.3 months) and progression-free survival (4.27 months) in adult patients with metastatic colorectal carcinoma (mCRC) with the BRAFV600E mutation compared to standard treatments, showing a hazard ratio of 0.61 for overall survival and 0.44 for progression-free survival.

The most common side effects reported with this treatment combination include fatigue, nausea, and skin-related issues, indicating that while the treatment is effective, it does come with a range of manageable adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy. Trullas, A., Delgado, J., Koenig, J., et al.[2021]

In the BEACON CRC study involving 216 patients with BRAFV600E-mutated metastatic colorectal cancer, the combination of encorafenib and cetuximab was generally well tolerated, with most adverse events being mild to moderate in severity and resolving quickly, typically within 1-2 weeks.

The most common adverse events included dermatological toxicity (75.5%), arthralgia/myalgia (56.0%), and fatigue/asthenia (56.0%), with notable survival benefits observed in patients experiencing these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAFV600E-mutant Metastatic Colorectal Cancer: An in-depth Analysis of the BEACON CRC Study. Taieb, J., Lonardi, S., Desai, J., et al.[2023]

Cetuximab and panitumumab are effective treatments for patients with previously untreated RAS wild-type metastatic colorectal cancer, showing cost-effectiveness when combined with standard chemotherapy regimens (FOLFOX or FOLFIRI) compared to chemotherapy alone.

Both drugs meet the National Institute for Health and Care Excellence's end-of-life criteria and are recommended for use within the UK National Health Service, indicating their potential benefit for patients not eligible for liver resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. Tikhonova, IA., Huxley, N., Snowsill, T., et al.[2021]

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Cetuximab - StatPearls - NCBI Bookshelf - NIH Colorectal cancer, metastatic, KRAS wild-type (without mutation) - Cetuximab improves both overall survival and progression-free survival and ...