Abemaciclib + Fluorouracil for Colorectal Cancer

Recruiting at 5 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

Trial Summary

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.

What data supports the effectiveness of the drug combination Abemaciclib and 5-Fluorouracil for colorectal cancer?

Research shows that 5-Fluorouracil (5-FU), when combined with folinic acid, is effective in treating metastatic colorectal cancer, improving response rates and survival compared to 5-FU alone. This suggests that 5-FU is a key component in effective colorectal cancer treatment, which may support its use in combination with other drugs like Abemaciclib. ^{1 2 3 4 5}

What safety data exists for 5-Fluorouracil in colorectal cancer treatment?

5-Fluorouracil (5-FU) used in colorectal cancer treatment can cause side effects like low blood cell counts (leucopenia, neutropenia, thrombocytopenia), mouth sores, diarrhea, nausea, vomiting, and hand-foot syndrome (redness and swelling of the hands and feet). These side effects are common but can be managed to allow patients to continue treatment. ^{6 7 8 9 10}

What makes the drug combination of Abemaciclib and 5-Fluorouracil unique for colorectal cancer?

The combination of Abemaciclib, a CDK4/6 inhibitor that blocks cancer cell division, with 5-Fluorouracil, a chemotherapy drug that disrupts DNA synthesis, offers a novel approach by targeting cancer cells through different mechanisms, potentially enhancing treatment effectiveness compared to standard chemotherapy alone. ^{2 3 8 11 12}

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of abemaciclib in combination with 5-fluorouracil and how well it works in treating patients with colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and that has not responded to treatment (refractory). Abemaciclib, a type of cyclin-dependent kinase inhibitor, blocks certain proteins, which may help keep tumor cells from growing. 5-fluorouracil, a type of antimetabolite, stops cells from making deoxyribonucleic acid (DNA) and may kill tumor cells. Giving abemaciclib in combination with 5-fluorouracil may be safe, tolerable, and/or effective in treating patients with metastatic and refractory colorectal cancer.

Research Team

Janie Y Zhang

Principal Investigator

UPMC Hillman Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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 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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Modified Irinotecan/5FU/Leucovorin therapy in advanced colorectal cancer and predicting therapeutic efficacy by expression of tumor-related enzymes. [2019]

2. Hungary pubmed.ncbi.nlm.nih.gov

[The modern treatment of colorectal cancer. Present and future]. [2018]

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

Increasing doses of 5-fluorouracil and high-dose folinic acid in the treatment of metastatic colorectal cancer. [2022]

4. England 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. [2020]

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

A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. [2017]

6. England 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? [2014]

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

S-1 and 5-Fluorouracil-related adverse events in patients with advanced gastric cancer: A meta-analysis. [2023]

8. United States 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. [2017]

9. England pubmed.ncbi.nlm.nih.gov

Molecularly targeted therapy: toxicity and quality of life considerations in advanced colorectal cancer. [2013]

10. Canada 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. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Update on capecitabine in colorectal cancer. [2015]

12. England 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. [2022]