ZN-c3 Combo for Metastatic Colorectal Cancer

No longer recruiting at 33 trial locations

Overseen By K-Group Beta, Inc. a subsidiary of Zentalis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

Disqualifiers: Symptomatic brain metastasis, Cardiovascular diseases, HIV, others

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

Compensation: Varies

Number of Visits: 16

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to assess the safety and effectiveness of a new treatment combination for individuals with advanced colorectal cancer. The treatment includes three drugs: ZN-c3 (Azenosertib), encorafenib (Braftovi), and cetuximab (Erbitux). It targets cancer with a specific gene change called BRAF V600E, particularly in patients whose cancer has worsened after one or two previous treatments. Individuals with metastatic colorectal cancer and this gene change, who have experienced disease progression after earlier treatments, might be suitable candidates for the trial. Participants will receive varying doses of these drugs to determine the optimal treatment plan. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that ZN-c3 was safe and well-tolerated in past studies involving patients with various solid tumors. Notably, ZN-c3 produced positive results even for patients who had undergone many previous treatments, and no unexpected safety issues emerged in these studies.

For encorafenib, research indicates it is generally safe when combined with cetuximab. This combination has been tested and did not introduce any new safety problems. Patients using this combination have experienced side effects that doctors know how to manage.

Cetuximab is already FDA-approved for treating colorectal cancer and has a well-known safety profile, meaning doctors understand the usual side effects and how to handle them.

Overall, the treatments in this trial, including ZN-c3, encorafenib, and cetuximab, have been tested in various settings and shown to be tolerable, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ZN-c3, Cetuximab, and Encorafenib for metastatic colorectal cancer because it offers a novel approach compared to current standard treatments like FOLFOX or FOLFIRI, which are chemotherapy-based. Unlike these traditional options, ZN-c3 is an investigational drug that works as a Wee1 inhibitor, potentially enhancing cancer cell death when combined with Encorafenib, a BRAF inhibitor, and Cetuximab, an EGFR inhibitor. This targeted therapy approach aims to effectively disrupt cancer cell growth and survival pathways, offering the promise of improved outcomes for patients with specific genetic mutations in their tumors.

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

This trial will evaluate the combination of ZN-c3 with encorafenib and cetuximab for treating advanced colorectal cancer with the BRAF V600E mutation. Research has shown that encorafenib and cetuximab, already used together for this specific cancer type, produce better results than other treatments. Adding ZN-c3, which blocks a protein that aids cancer cell repair, aims to enhance the treatment's effectiveness. Early findings suggest this combination might further slow tumor growth. Although all results are still under review, these early signs are encouraging. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

Adults with metastatic colorectal cancer that has a specific mutation (BRAF V600E) and who have tried 1 or 2 other treatments without success. They must have measurable disease, good bone marrow, liver, and kidney function. Not eligible if pregnant/breastfeeding, have serious heart issues, another cancer within the last 2 years, brain metastasis or certain infections.

Inclusion Criteria

My liver and kidneys are working well.

My cancer has worsened after 1 or 2 treatments for its spread.

My bone marrow is working well.

Exclusion Criteria

I have not had another type of cancer in the past 2 years.

I have received a transplant from another person.

I have an active hepatitis B or C infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive different doses of ZN-c3 in combination with different doses of Encorafenib and a fixed dose of Cetuximab to determine the recommended dose

Up to 12 months

Every 8 weeks

Dose Expansion

Participants receive the recommended dose of ZN-c3 and Encorafenib in combination with Cetuximab to evaluate safety and efficacy

Up to 12 months

Every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Encorafenib
• ZN-c3

Trial Overview

The trial is testing ZN-c3 in combination with encorafenib and cetuximab to see if they're safe together and can help patients whose colorectal cancer has spread. Participants will already have had previous treatments that didn't work well enough.

How Is the Trial Designed?

Group I: Dose Expansion Experimental Treatment 3 Interventions

Participants will receive recommended dose of ZN-c3 and encorafenib as determined in dose escalation phase in combination with cetuximab

Group II: Dose Escalation Experimental Treatment 3 Interventions

Participants will receive different doses of ZN-c3 in combination with different doses of Encorafenib and a fixed dose of Cetuximab

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?

K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

Lead Sponsor

Trials

8

Recruited

740+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

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]

Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor, which plays a crucial role in the growth of various cancers.

It received accelerated approval from the US FDA in February 2004 for treating metastatic colorectal cancer based on positive tumor response rates observed in Phase II clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab. Goldberg, RM.[2020]

In the BEACON CRC clinical trial, the combination of encorafenib and cetuximab significantly improved median overall survival and progression-free survival in adults with metastatic colorectal cancer harboring a BRAF V600E mutation, compared to standard therapies.

The treatment was found to have a manageable safety profile, making it a promising targeted option for patients who have already undergone previous systemic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. Al-Salama, ZT.[2021]

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]

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 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 and panitumumab, both targeting the EGFR, have been shown to improve progression-free and overall survival in patients with wild-type RAS metastatic colorectal cancer, highlighting their efficacy as treatment options.

Common side effects include dermatological issues like acneiform rash and hair changes, which are important to consider alongside the cost-effectiveness of these therapies in routine clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of EGFR inhibitors in colorectal cancer: is it clinically efficacious and cost-effective? Lien, K., Berry, S., Ko, YJ., et al.[2018]

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