ZEN003694 + Chemotherapy for Colorectal Cancer

Recruiting at 22 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Capecitabine

Must not be taking: BET inhibitors, Factor Xa inhibitors

Disqualifiers: CNS disease, DPD deficiency, others

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

Compensation: Varies

Number of Visits: 4

Duration: 21 days per cycle

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with the usual treatment with capecitabine in treating patients with cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable) and that it has progressed on previous standard treatment. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce BET protein. Capecitabine is in a class of medications called antimetabolites. It is taken up by cancer cells and breaks down into fluorouracil, a substance that kills cancer cells. Giving ZEN003694 in combination with capecitabine may be safe in treating patients with metastatic or unresectable solid tumors.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot take certain blood thinners or medications that strongly affect liver enzymes (CYP3A4). You should discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug ZEN003694 + Chemotherapy for Colorectal Cancer?

Capecitabine, a component of the treatment, has been shown to be effective in treating colorectal cancer, with studies indicating it is at least as effective as traditional 5-FU therapy and associated with fewer side effects. Additionally, capecitabine has demonstrated superior response rates and improved relapse-free survival in various trials. ^{1 2 3 4 5}

Is the combination of ZEN003694 and chemotherapy safe for humans?

Capecitabine (also known as Xeloda) has been studied for safety in various cancers, including colorectal cancer. It is generally safe but can cause side effects like nausea, diarrhea, and hand-foot syndrome (redness and swelling of the hands and feet). ^{1 2 5 6 7}

What makes the drug ZEN003694 + Capecitabine unique for colorectal cancer?

The combination of ZEN003694 with Capecitabine is unique because Capecitabine is an oral drug that is selectively activated in tumor cells, mimicking continuous infusion of 5-FU but with more convenience and potentially fewer side effects. ZEN003694 is a novel addition that may enhance the effectiveness of Capecitabine, offering a new approach to treatment. ^{1 2 3 5 7}

Research Team

Dennis Hsu

Principal Investigator

University of Pittsburgh Cancer Institute LAO

Eligibility Criteria

This trial is for adults with metastatic or unresectable cancers that have worsened after standard treatment, including fluorouracil or capecitabine. Participants must be HIV-positive on effective therapy, if applicable, and cannot have used BET inhibitors before. They should not have severe illnesses that could interfere with the study and must agree to use contraception.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

I am willing and able to have biopsies before and during treatment.

Total bilirubin =< 1.5 institutional upper limit of normal (ULN)

Exclusion Criteria

I have a stomach or intestine condition that affects how I absorb pills.

I have a known DPD deficiency.

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

Timeline

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 and capecitabine orally twice daily, 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle

Regular visits for CT/MRI, PET/CT, and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up for safety 30 days after the last dose, and then every 3 months for 12 months.

12 months

Follow-up visits every 3 months

Treatment Details

Interventions

• Capecitabine
• ZEN003694

Trial Overview The trial is testing ZEN003694 combined with usual chemotherapy (capecitabine) to see if it's safe and what the best dose might be for treating advanced solid tumors. ZEN003694 targets proteins involved in tumor growth, while capecitabine interferes with cancer cell DNA.

Participant Groups

Group I: Treatment (ZEN003694, capecitabine) Experimental Treatment 7 Interventions

Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.

Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 45 patients with locally advanced rectal cancer, preoperative chemoradiation using capecitabine resulted in significant tumor downstaging, with 63% of primary tumors and 90% of lymph nodes showing downstaging, and a pathologic complete response in 31% of patients.

The treatment was found to be safe and well-tolerated, with no severe hematologic toxicities and manageable Grade 3 side effects, suggesting that capecitabine can effectively enhance surgical options, including sphincter-preserving surgeries for tumors near the anal verge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Kim, JS., Kim, JS., Cho, MJ., et al.[2022]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

Capecitabine, a pro-drug converted to 5-fluorouracil in cancer cells, has shown superior response rates compared to traditional 5-FU in metastatic colorectal cancer, with similar overall survival outcomes.

In the adjuvant setting, capecitabine improved relapse-free survival and had fewer adverse events than the combination of 5-FU and leucovorin, leading to its approval as a standard treatment for stage III colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of capecitabine in management of early colon cancer. Hameed, H., Cassidy, J.[2021]

Xeloda (capecitabine) is an oral pro-drug that is effectively converted to 5-fluorouracil in the body, particularly in colorectal cancer, where the enzyme needed for activation is more active.

In large phase III trials, capecitabine demonstrated at least equal efficacy to the standard intravenous treatment of 5-FU and leucovorin, with better response rates and significantly lower toxicity, suggesting it may become the preferred treatment for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xeloda in colorectal cancer. Cassidy, J.[2015]

In a study of 44 previously untreated patients with advanced gastric cancer, capecitabine demonstrated an objective response rate of 34% and a median overall survival of 9.5 months, indicating its efficacy as a first-line treatment.

Capecitabine was generally well tolerated, with the most common side effects being hand-foot syndrome and nausea, and severe myelosuppression was not observed, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Hong, YS., Song, SY., Lee, SI., et al.[2022]

In a study of 42 patients with advanced breast and colorectal cancer, capecitabine showed a partial response rate of 29.16% for breast cancer and 11.76% for colorectal cancer, indicating its potential efficacy in these pretreated patients.

Capecitabine was well tolerated with low toxicity levels, as most adverse reactions were mild, although 7.14% of patients experienced grade 3 hand-foot syndrome, and hypertriglyceridemia was noted in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. Stathopoulos, GP., Koutantos, J., Lazaki, H., et al.[2022]

In a study of 19 colorectal cancer patients, capecitabine was shown to preferentially convert to 5-fluorouracil (5-FU) in tumor tissues, with 5-FU concentrations in tumors being 3.2 times higher than in adjacent healthy tissues, indicating effective targeting of the drug.

The enzyme thymidine phosphorylase (TP) plays a crucial role in this preferential activation, being significantly more active in colorectal tumors compared to healthy tissue, which helps explain the enhanced efficacy of capecitabine in treating colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Schüller, J., Cassidy, J., Dumont, E., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. [2022]

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

Use of capecitabine in management of early colon cancer. [2021]

4. India pubmed.ncbi.nlm.nih.gov

Xeloda in colorectal cancer. [2015]

5. England pubmed.ncbi.nlm.nih.gov

A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. [2022]