Abemaciclib + Fluorouracil for Colorectal Cancer

Recruiting at 11 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Pregnancy, CDK4/6 inhibitors, others

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

Compensation: Varies

Number of Visits: 3

Duration: 28 days per cycle, repeated until disease progression or unacceptable toxicity

39 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new drug combination to treat metastatic colorectal cancer unresponsive to existing treatments. The goal is to determine a safe and effective dose of abemaciclib, which inhibits cancer cell growth, combined with 5-fluorouracil, which destroys tumor cells. Individuals with colorectal cancer unresponsive to standard treatments may qualify for this study. 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 combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does require a washout period (time without taking certain medications) of two weeks or five half-lives, whichever is shorter, for investigational agents. Additionally, you cannot take strong inhibitors or inducers of CYP3A enzymes while participating in the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that using abemaciclib with 5-fluorouracil might be safe and manageable for people with advanced colorectal cancer. Earlier studies indicate that patients generally handle this combination well, with manageable side effects.

Abemaciclib blocks certain proteins that help cancer cells grow. It has been used in other conditions and is known to be fairly well-tolerated. In contrast, 5-fluorouracil stops cancer cells from making DNA, which they need to grow.

Both drugs have been studied separately and together. Common side effects include nausea or tiredness, but these are usually not severe. As this is an early-phase trial, the main goal is to carefully monitor patient reactions to the combination and determine the safest dose. ^{1 2 3 4 5}

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

Researchers are excited about the combination of Abemaciclib and 5-Fluorouracil for colorectal cancer because it introduces a novel approach to treatment by combining a CDK4/6 inhibitor with a chemotherapy agent. Abemaciclib specifically targets proteins that are involved in cell division, potentially halting the growth of cancer cells more effectively than traditional chemotherapy alone. This combination could enhance the effectiveness of treatment and possibly reduce tumor progression compared to existing options like FOLFOX or FOLFIRI, which primarily rely on chemotherapy alone. This innovative treatment strategy offers hope for improved outcomes by targeting cancer cells in a new way.

What evidence suggests that this treatment might be an effective treatment for metastatic colorectal cancer?

In this trial, participants will receive a combination of abemaciclib and 5-fluorouracil to treat colorectal cancer that has spread or is difficult to treat. Research has shown that abemaciclib blocks proteins that help cancer cells grow, and early studies suggest it can arrest cancer cells in one stage of growth, slowing their spread. 5-fluorouracil prevents cancer cells from making DNA, which can kill them. Together, these drugs may more effectively target cancer cells. Although more research is needed, early findings suggest this combination could be a promising option for difficult-to-treat colorectal cancer. ^{2 3 6 7 8}

Who Is on the Research Team?

Janie Y Zhang

Principal Investigator

UPMC Hillman Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with metastatic colorectal cancer that's spread and hasn't improved with standard treatments. They must have a certain level of blood cells, kidney function, liver health, and be physically able to handle the trial activities. Children and those not meeting these health requirements can't join.

Inclusion Criteria

Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2

Platelets ≥ 100,000/mcL

Patients must have measurable disease

Exclusion Criteria

I am taking medication that strongly affects liver enzyme levels.

History of allergic reactions to compounds similar to abemaciclib or other study agents

Pregnant or breastfeeding women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive abemaciclib orally twice daily and 5-FU intravenously over 46 hours on days 1 and 15 of each 28-day cycle

28 days per cycle, repeated until disease progression or unacceptable toxicity

Regular visits for blood sample collection and radiologic imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Follow-up every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• 5-Fluorouracil
• Abemaciclib

Trial Overview The trial is testing Abemaciclib combined with usual chemotherapy (5-Fluorouracil) to see if it's safe and effective for treating advanced colorectal cancer that hasn't responded to other treatments. It will also determine the best dose of Abemaciclib.

How Is the Trial Designed?

Group I: Treatment (abemaciclib, 5-FU) Experimental Treatment 5 Interventions

Patients receive abemaciclib PO BID on days 1-28 and 5-FU IV over 46 hours on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and radiologic imaging throughout the study and may additionally undergo a tissue biopsy before treatment and on cycle 1 day 16.

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 review of 8 randomized controlled trials involving 3,455 patients with advanced gastric cancer, S-1 was associated with fewer severe adverse events compared to 5-fluorouracil (5-FU), particularly showing lower rates of stomatitis, hypokalemia, mucosal inflammation, and hypophosphatemia.

Both S-1 and 5-FU have side effects, but the findings suggest that S-1 may be a safer option for patients, highlighting the need for healthcare providers to monitor and manage adverse events effectively to enhance patient compliance and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 and 5-Fluorouracil-related adverse events in patients with advanced gastric cancer: A meta-analysis. Hu, Q., Xu, J., Ke, J., et al.[2023]

The combination of 5-fluorouracil-based regimens with molecularly targeted agents has significantly expanded treatment options for patients with metastatic colorectal cancer, which is crucial given its status as a leading cause of cancer-related death.

Proactive management of adverse events associated with these treatments can lead to uninterrupted therapy and improved quality of life for patients, as the efficacy of the treatment helps prolong wellness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecularly targeted therapy: toxicity and quality of life considerations in advanced colorectal cancer. Ribecco, AS., Pino, MS., Cipriani, G., et al.[2013]

The combination of traditional chemotherapy agents like fluorouracil (5FU) with newer drugs such as irinotecan and oxaliplatin has significantly improved treatment effectiveness for colorectal cancer, leading to better patient outcomes.

Emerging targeted therapies are showing promise in reducing toxicity compared to traditional chemotherapy, and their integration into treatment protocols may extend survival rates for metastatic colorectal cancer patients from 2 to potentially 3 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The modern treatment of colorectal cancer. Present and future]. András, C., Farczádi, E., Szántó, J.[2018]

In a study of 1033 colorectal cancer patients treated with 5-fluorouracil (5FU) based adjuvant therapy, certain adverse events like neutropenia, nausea/vomiting, and mucositis were linked to better disease-free survival (DFS) and overall survival (OS).

Patients who experienced any grade of neutropenia had a 19% lower risk of disease progression, while those with nausea/vomiting had a 38% lower risk of death, suggesting that these adverse effects may serve as positive indicators of treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of adverse events and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil and leucovorin: Is efficacy an impact of toxicity? Soveri, LM., Hermunen, K., de Gramont, A., et al.[2014]

Oral 5-fluorouracil (capecitabine) can effectively replace intravenous 5-FU in chemotherapy for metastatic colorectal cancer without increasing overall toxicity or significantly reducing treatment efficacy, based on preclinical and early clinical studies.

Capecitabine combined with radiation shows promising results in achieving high rates of pathological complete response in rectal cancer, although careful management of its potential toxicities is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on capecitabine in colorectal cancer. Schmoll, HJ., Arnold, D.[2015]

In a study involving 105 patients with metastatic colorectal cancer, arfolitixorin was found to be well-tolerated and showed potential to enhance the efficacy of 5-fluorouracil (5-FU), with 15.8% of patients achieving a partial response after 8 weeks of treatment.

Arfolitixorin, an immediately active form of folate, may improve treatment outcomes, especially in patients with low folate pathway gene expression, and can be easily integrated into existing chemotherapy regimens with minimal adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer. Carlsson, G., Koumarianou, A., Guren, TK., et al.[2022]

In a phase II trial involving 100 patients with metastatic colorectal cancer, an intensified chronomodulated schedule of fluorouracil (5-FU) and l-folinic acid (l-FA) resulted in a 41% objective response rate, indicating significant efficacy as a first-line treatment.

The treatment was generally tolerable, with 66% of patients able to escalate their 5-FU dose, though some experienced grade 3 to 4 toxicities such as hand-foot syndrome and mucositis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer. Curé, H., Chevalier, V., Adenis, A., et al.[2017]

In a study of 75 patients with metastatic colorectal cancer, the combination of oral 5-fluorouracil (5-FU) and eniluracil showed some efficacy, particularly in previously untreated patients, with partial responses observed in 5 out of 24 patients.

The treatment was generally well tolerated, with mild non-hematologic toxicities; however, myelosuppression was common, leading to neutropenic sepsis in 13.5% of patients, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer. Schilsky, RL., Bukowski, R., Burris, H., et al.[2020]

In a study of 32 patients with metastatic colorectal cancer, individualized weekly dosing of 5-fluorouracil (5FU) combined with folinic acid (FA) led to a 36.7% objective response rate and a median survival of 22 months for responders.

The study found that 87.5% of patients tolerated doses of 720 mg/m2 or more, but increasing the dose beyond this did not improve effectiveness and resulted in severe side effects, indicating that 720 mg/m2 is a critical threshold for maximizing treatment benefits while minimizing risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increasing doses of 5-fluorouracil and high-dose folinic acid in the treatment of metastatic colorectal cancer. Meregalli, M., Martignoni, G., Frontini, L., et al.[2022]

In a study of 21 patients with advanced or recurrent colorectal cancer, a treatment regimen combining Irinotecan, 5FU, and Leucovorin resulted in a good response rate of 43% and a mean survival time of 15.7 months, indicating its potential efficacy.

The study identified predictive factors related to chemotherapy response, such as low levels of DPD mRNA in tumors being associated with longer survival, which could help tailor individualized treatment plans for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified Irinotecan/5FU/Leucovorin therapy in advanced colorectal cancer and predicting therapeutic efficacy by expression of tumor-related enzymes. Yanagisawa, Y., Maruta, F., Iinuma, N., et al.[2019]

In a randomized controlled trial involving 130 patients with recurrent or metastatic colon or rectal cancer, the combination of fluorouracil (5-FU) and folinic acid (FA) significantly improved response rates (33% vs. 7%) compared to 5-FU alone.

Patients receiving the combination treatment also experienced longer overall survival (12.6 months) compared to those on 5-FU alone (9.6 months), indicating that 5-FU and FA is an effective option for patients who have not undergone prior chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. Erlichman, C., Fine, S., Wong, A., et al.[2017]

In a study of 110 Asian patients with metastatic colorectal cancer, those treated with the mFOLFOX6 regimen including a 5-FU bolus had a significantly lower absolute neutrophil count (ANC) compared to those who did not receive the bolus, indicating a potential risk for neutropenia.

The findings suggest that omitting the 5-FU bolus from the mFOLFOX6 regimen may be necessary for patients at high risk of hematological adverse events, particularly neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer. Areepium, N., Sapapsap, B.[2023]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-08691

Testing the Addition of an Anti-Cancer Drug, Abemaciclib ... Giving abemaciclib in combination with 5-fluorouracil may be safe, tolerable, and/or effective in treating patients with metastatic and refractory colorectal ...

2. trials-api.montefioreeinstein.org trials-api.montefioreeinstein.org/node/413301

Testing the Addition of an Anti-Cancer Drug, Abemaciclib ... Giving abemaciclib in combination with 5-fluorouracil may be safe, tolerable, and/or effective in treating patients with metastatic and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11242104/

Synergistic Enhancement of Antitumor Effects by ... Single treatment with abemaciclib increased the G1 population in HCT-116 cells, as the concentration was increased from G1-23.5% at a negative control to 57.8% ...

4. journals.sagepub.com journals.sagepub.com/doi/10.1177/17588359241286775

Abemaciclib combined with endocrine therapy as adjuvant ... With a median follow-up of 53 months, the addition of abemaciclib to ET resulted in improvements in IDFS (estimated 5-year IDFS rate: 85.9% vs ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2666776225002637

Prevalence and prognosis of patients with breast cancer ... While the two trials investigating palbociclib, PALLAS and PENELOPE-B,, were negative for the primary endpoint, monarchE (abemaciclib) and NATALEE (ribociclib) ...

6. ucihealth.org ucihealth.org/clinical-trials/etctn-10670

A Phase I Study of 5-Fluorouracil in Combination ... Giving abemaciclib in combination with 5-fluorouracil may be safe, tolerable, and/or effective in treating patients with metastatic and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9808480/

Antitumor activity of lurbinectedin in combination with oral ... The capecitabine/lurbinectedin combination showed encouraging clinical activity in relapsed MBC, especially in HR-positive tumors.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT07042685

Study Details | NCT07042685 | Trial of 5-Fluorouracil (5FU) ... This is a phase II trial investigating the efficacy and safety of 5-Fluorouracil (5FU)-based therapy in combination with fruquintinib for patients with locally ...