Genetically Guided Epirubicin Dosing for Breast Cancer

Overseen By Denise Brown, RN MN

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Disqualifiers: Congestive heart failure, Angina, Myocardial infarction, Psychiatric disorders, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the chemotherapy drug epirubicin, used to treat breast cancer. Typically, doctors determine the dosage based on a person's height and weight. However, this study aims to assess whether using genetic information provides a better approach. The trial includes women with non-metastatic breast cancer who are already scheduled for specific chemotherapy treatments. Participants will undergo a genetic test, and based on the results, they may receive a different dose of epirubicin during some treatment cycles. This method could lead to more personalized and effective cancer care. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to advancements in personalized cancer therapy.

Do I need to stop my current medications for this trial?

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 treatment is likely to be safe for humans?

Research has shown that epirubicin, a chemotherapy drug for breast cancer, has undergone safety testing over many years. Studies have found that standard doses can be effective without causing additional side effects. Safety data indicates that the risk of heart problems, known as cardiomyopathy, increases with the total amount of the drug taken. For instance, heart issues occur in less than 2% of people at certain dose levels.

Overall, past research considers epirubicin to be well-tolerated and it has been used safely in various breast cancer treatments. The current study aims to determine if adjusting the dose based on a person's genetics is more effective than using just their height and weight. This approach could tailor the treatment to each person, potentially making it safer and more effective. ^{1 2 3 4 5}

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

Most treatments for breast cancer, like standard chemotherapy drugs, are given in fixed doses without considering individual genetic differences. But this new approach with epirubicin is different because it uses genetic analysis to tailor the dosage for each patient. By adjusting the dose based on genetic markers, researchers hope to optimize the drug’s effectiveness while minimizing side effects. This personalized strategy could lead to more effective treatments with fewer adverse effects, which is why researchers are excited about this potential breakthrough in breast cancer therapy.

What evidence suggests that genetically guided epirubicin dosing might be an effective treatment for breast cancer?

Research has shown that epirubicin effectively treats breast cancer. Studies have found that patients with advanced breast cancer often respond positively to this treatment. Specifically, 62% of patients did not experience a return of cancer after five years, and 77% were still alive. In this trial, genetic testing will guide epirubicin dosing, allowing for adjustments based on individual genetic traits. Participants may receive either standard or increased doses depending on their genetic analysis, aiming to tailor chemotherapy to each person for better effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Michael B Sawyer, MD FRCPC BScPharm

Principal Investigator

Alberta Health services

John R Mackey, MD FRCPC

Principal Investigator

Alberta Health services

Are You a Good Fit for This Trial?

This trial is for women with non-metastatic invasive breast cancer, scheduled for specific chemo. They must have a good performance status, confirmed hormone receptor status, and a healthy heart function (LVEF ≥ 50%). It's not for those with recent heart attacks, uncontrolled heart conditions or severe psychiatric disorders.

Inclusion Criteria

I can do most of my daily activities on my own.

I am a woman with breast cancer set to receive FEC100 treatment.

My breast cancer has been tested for hormone receptor status.

Exclusion Criteria

I do not have severe heart issues like recent heart attacks or uncontrolled heart failure.

Psychiatric disorder(s) that would interfere with consent, study participation, or follow up

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Genetic Analysis

Participants undergo genetic analysis to determine epirubicin dosing

1-2 weeks

Treatment

Participants receive epirubicin dosing based on genetic profiles for cycles 2-4

6-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Epirubicin

Trial Overview The study tests if dosing the chemotherapy drug Epirubicin based on genetic profiles leads to better outcomes than the standard method of dosing by height and weight in breast cancer treatment.

How Is the Trial Designed?

Group I: Epirubicin Experimental Treatment 1 Intervention

Following genetic analysis, depending on results, participants will receive either standard or increased epirubicin dosing for cycles 2 - 4.

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

Approved in United States as Ellence for:

• Breast cancer

Approved in European Union as Pharmorubicin for:

• Breast cancer
• Ovarian cancer
• Soft tissue sarcoma
• Superficial bladder cancer

Approved in Canada as Epirubicin for:

• Breast cancer

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Published Research Related to This Trial

Epirubicin, when used in combination with cyclophosphamide and 5-fluorouracil for adjuvant chemotherapy in 10 patients with Stage 2 breast cancer, showed a manageable toxicity profile, primarily causing moderate granulocytopenia without any cases of granulocytopenic fever.

While some patients experienced significant side effects like vomiting and hair loss, the absence of severe cardiac issues suggests that epirubicin may be less cardiotoxic than doxorubicin, indicating its potential for further evaluation in breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) for stage II breast cancer. Jones, SE., Mennel, RG., Peters, GN., et al.[2019]

Epirubicin, an anthracycline analogue, is less cardiotoxic than doxorubicin, allowing for higher cumulative doses (950-1000 mg/m2) to be safely administered in the treatment of metastatic breast cancer.

In a phase II study involving 36 patients, a combination of gemcitabine, epirubicin, and paclitaxel resulted in a high overall response rate of 92% and a complete response rate of 31%, indicating its effectiveness as a first-line treatment while being well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of epirubicin in advanced breast cancer. Conte, PF., Gennari, A., Landucci, E., et al.[2019]

A new dosing scheme for epirubicin in women with breast cancer and liver dysfunction was developed, showing that adjusting the dose based on aspartate aminotransferase (AST) levels can lead to safer and more effective treatment outcomes.

In a study involving 41 women with elevated AST, adaptive dosing resulted in lower variability in drug concentration levels compared to standard dosing, suggesting that this method may enhance the predictability of epirubicin's effects in patients with liver issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epirubicin in patients with liver dysfunction: development and evaluation of a novel dose modification scheme. Dobbs, NA., Twelves, CJ., Gregory, W., et al.[2019]

In a pilot phase II trial involving 35 patients with metastatic breast cancer, the combination of epirubicin and paclitaxel showed a 43% response rate, with 7% achieving complete responses and 37% partial responses, indicating its efficacy in this patient population.

The treatment was associated with significant hematologic toxicity, particularly grade 4 neutropenia in 91% of patients, necessitating dose reductions for some, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of epirubicin plus paclitaxel in metastatic breast cancer. United Kingdom Coordinating Committee for Cancer Research Breast Cancer Sub-Committee. Carmichael, J., Jones, A., Hutchinson, T.[2015]

Epirubicin demonstrated significant antitumor activity in advanced breast cancer, achieving a 69% overall response rate (2 complete responses and 13 partial responses) in a study of 22 patients, with a mean treatment duration of 61 weeks.

While some patients experienced mild cardiotoxicity and severe alopecia, epirubicin was well-tolerated overall, with no acute toxicity-related deaths and manageable hematological side effects, indicating it is a safer alternative to traditional anthracyclines like doxorubicin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epirubicin high-dose therapy in advanced breast cancer: preliminary clinical data. Epirubicin as a single agent in breast cancer. Neri, B., Pacini, P., Bartalucci, S., et al.[2013]

In a study of 64 patients with locally advanced or metastatic breast cancer, a combination treatment including epirubicin allowed for dose escalation up to 120 mg/m², leading to a high overall response rate of 72% in metastatic cases, with a 25% complete response rate.

The use of granulocyte colony-stimulating factor (G-CSF) helped prevent neutropenia, but the treatment was associated with significant cumulative bone marrow toxicity, highlighting the need for careful monitoring of blood cell counts during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laevofolinic acid, 5-fluorouracil, cyclophosphamide and escalating doses of epirubicin with granulocyte colony-stimulating factor support in locally advanced and/or metastatic breast carcinoma: a phase I-II study of the Southern Italy Oncology Group (GOIM). Colucci, G., Romito, S., Gebbia, V., et al.[2019]

Epirubicin demonstrated a 44% overall response rate in 61 patients with advanced soft tissue sarcoma, with higher response rates observed at increased doses (17% at 140 mg/m², 44% at 160 mg/m², and 100% at 180 mg/m²).

The maximum-tolerated dose was determined to be 180 mg/m², but the recommended clinical dose is 160 mg/m² every 3 weeks, as it was safe and effective while minimizing severe side effects like myelosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increasing single epirubicin doses in advanced soft tissue sarcomas. Lopez, M., Vici, P., Di Lauro, L., et al.[2017]

Epirubicin is a highly effective treatment for breast cancer, showing improved response rates in advanced cases when used in higher doses or in combination with other agents like vinorelbine or paclitaxel.

While epirubicin has notable efficacy, it carries risks of significant side effects, including acute hematological toxicity and cumulative cardiac toxicity, although these are generally less severe than those associated with doxorubicin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epirubicin. An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer. Coukell, AJ., Faulds, D.[2018]

A comprehensive physiologically based pharmacokinetic (PBPK) model was developed to simulate epirubicin exposure in a cohort of 2000 cancer patients, revealing that individual differences in drug metabolism significantly affect plasma concentrations of epirubicin.

Key factors influencing variability in epirubicin exposure included hepatic and renal UGT2B7 expression, plasma albumin levels, age, body surface area (BSA), glomerular filtration rate (GFR), hematocrit, and sex, explaining 87% of the variability in drug exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution. Ansaar, R., Meech, R., Rowland, A.[2023]

In a study of 127 metastatic breast cancer patients treated with high-dose epirubicin (120 mg/m2 every 3 weeks), the overall response rate was 48%, with 11% achieving a complete response and 37% a partial response.

Despite its efficacy, 19% of patients experienced cardiotoxicity, highlighting the need for careful assessment of cardiac risk factors before administering high-dose epirubicin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single agent epirubicin as first line chemotherapy for metastatic breast cancer patients. Michelotti, A., Venturini, M., Tibaldi, C., et al.[2019]

Epirubicin showed limited efficacy as a single agent in treating melanoma and colorectal cancer, with only one complete response and three partial responses among 66 assessable patients, indicating it may not be effective for these cancers.

In head and neck cancer, epirubicin demonstrated an 18% response rate, suggesting potential for further investigation in combination therapies, despite notable toxicities such as myelosuppression and cardiac effects in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epirubicin has modest single-agent activity in head and neck cancer but limited activity in metastatic melanoma and colorectal cancer: phase II studies by the Eastern Cooperative Oncology Group. Rosenthal, MA., Green, M., Wiernik, P., et al.[2019]

Citations

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Genetically Guided Epirubicin Dosing for Breast Cancer Epirubicin is shown to be effective in treating breast cancer, with studies reporting high response rates in patients with advanced breast cancer. In ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01740271

A Study of Genetic Based Chemotherapy Dosing for Breast ... The purpose of this study is to see if epirubicin dosing based on people's genetic profiles is better than the usual methods.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1526820921000562

Uridine Glucuronosyltransferase 2B7 Polymorphism-Based ... This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6208899/

Predicting efficacy of epirubicin by a multigene assay in ... This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP ...

5. cancernetwork.com cancernetwork.com/view/panel-gives-nod-ellence-adjuvant-use-breast-cancer

Panel Gives Nod to Ellence for Adjuvant Use in Breast ... In the MA-5 study, the epirubicin arm had a 62% 5-year relapse-free survival rate and a 77% overall survival rate, compared with 53% and 70%, respectively, in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10791571/

Ten-year clinical outcome, toxicity and compliance of dose ... In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well ...

7. gs.amegroups.org gs.amegroups.org/article/view/49937/html

Standard-dose epirubicin increases the pathological complete ... Standard-dose epirubicin increases the pCR rate in breast cancer patients treated with NAC, and no other toxicity is noted.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0960977611004206

Epirubicin: Is it like doxorubicin in breast cancer? A clinical ... A 10-year follow-up revealed the superiority of six cycles of FEC 100 in terms of DFS (50.7% versus 45.3%), with a relative risk reduction of 24%, and similar ...

9. labeling.pfizer.com labeling.pfizer.com/showlabeling.aspx?id=657

ELLENCE (epirubicin hydrochloride injection) The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and ...

10. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11970749/

Role of epirubicin in advanced breast cancer We report findings of a trial of combination epirubicin/paclitaxel as first-line treatment of advanced breast cancer, with overall response rates (ORRs) of 84%.