ZN-c3 Combo for Metastatic Colorectal Cancer

Recruiting at 26 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

44 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety, tolerability, and potential clinical benefits of ZN-c3 administered in combination with encorafenib and cetuximab in adult participants with metastatic BRAF V600E mutant colorectal cancer previously treated with one or two treatment regimens.

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.

What data supports the effectiveness of the drug combination ZN-c3, Cetuximab, and Encorafenib for metastatic colorectal cancer?

Research shows that Cetuximab, when combined with other treatments like FOLFIRI or Encorafenib, improves survival and response rates in patients with metastatic colorectal cancer, especially those with specific genetic mutations. Encorafenib plus Cetuximab has been shown to significantly extend survival in patients with the BRAF V600E mutation. ^{1 2 3 4 5}

What safety data exists for the ZN-c3 Combo treatment for metastatic colorectal cancer?

Cetuximab, a part of the ZN-c3 Combo, has been used in treating metastatic colorectal cancer and is generally considered safe, but it can cause side effects like skin rash, fatigue, nausea, and diarrhea. Encorafenib, another component, when combined with cetuximab, has shown similar side effects. These treatments have been evaluated in various studies, confirming their safety profile in humans. ^{1 3 4 6 7}

What makes the ZN-c3 Combo drug unique for treating metastatic colorectal cancer?

The ZN-c3 Combo drug is unique because it combines cetuximab, which targets the epidermal growth factor receptor (EGFR), with encorafenib and ZN-c3, potentially offering a novel approach for patients with KRAS wild-type metastatic colorectal cancer, where cetuximab has shown improved survival rates when used with other treatments. ^{1 2 3 8 9}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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 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 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]

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]

References

1. New Zealand 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. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. [2021]

3. England pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

4. England 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. [2021]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Cetuximab. [2020]

7. England pubmed.ncbi.nlm.nih.gov

The use of EGFR inhibitors in colorectal cancer: is it clinically efficacious and cost-effective? [2018]

8. England pubmed.ncbi.nlm.nih.gov

Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab. [2023]

9. Japan pubmed.ncbi.nlm.nih.gov

[Cetuximab for patients with metastatic colorectal cancer-from the result of recent clinical trials]. [2016]