Chemotherapy + Trastuzumab for Breast Cancer

Recruiting at 1420 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anthracyclines, Taxanes, Trastuzumab, others

Disqualifiers: Metastatic disease, Cardiac disease, Hypertension, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 9

Duration: 1 year

3270 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications, such as endocrine therapy (like tamoxifen) and sex hormonal therapy (like birth control pills), before joining. If you are on these medications, you must discontinue them prior to randomization.

What evidence supports the effectiveness of the drug combination of chemotherapy and trastuzumab for breast cancer?

Research shows that combining doxorubicin and docetaxel, both part of the chemotherapy regimen, is highly effective in treating advanced breast cancer, with higher response rates compared to other treatments. Additionally, trastuzumab, when combined with chemotherapy, has been shown to improve response rates and prolong the time to disease progression in HER2-positive breast cancer patients. ^{1 2 3 4 5}

Is the combination of chemotherapy drugs like docetaxel, doxorubicin, and cyclophosphamide safe for treating breast cancer?

The combination of docetaxel, doxorubicin, and cyclophosphamide (TAC) is generally considered safe for treating breast cancer, though it can cause side effects like neutropenia (low white blood cell count), which can lead to infections. Cardiac issues are rare, and other side effects like fluid retention and nail changes are usually mild. With proper management, these side effects are typically manageable. ^{5 6 7 8 9}

What makes the chemotherapy and trastuzumab combination unique for breast cancer treatment?

This treatment combines chemotherapy drugs with trastuzumab, a targeted therapy that specifically attacks cancer cells overexpressing the HER-2 protein, which is common in some breast cancers. This combination has shown higher response rates and longer time to disease progression compared to chemotherapy alone, although it can increase the risk of heart-related side effects. ^{2 10 11 12 13}

What is the purpose of this trial?

This randomized phase III clinical trial studies chemotherapy with or without trastuzumab after surgery to see how well they work in treating women with invasive breast cancer. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) and giving chemotherapy after surgery may kill more tumor cells. Monoclonal antibodies, such as trastuzumab, can block cancer growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether combination chemotherapy is more effective with trastuzumab in treating breast cancer.

Research Team

Louis Fehrenbacher

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for women with invasive breast cancer who've had surgery. They must have a life expectancy of at least 10 years, not counting their cancer, and be in good health otherwise. Participants need proper organ function and no history of certain cancers or treatments within the last 5 years. Women must agree to avoid pregnancy during and after the trial for specified periods.

Inclusion Criteria

Your kidney function test within 6 weeks before the study must be within the normal range.

You have signed a consent form that has been approved by a review board and follows the rules set by the government and institution.

My cancer's HER2 status has been checked.

Exclusion Criteria

I have had breast cancer in both breasts at the same time or at different times.

Use of any investigational product within 30 days prior to randomization

I am currently on hormone therapy for my cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive chemotherapy with or without trastuzumab. Chemotherapy regimens include docetaxel and cyclophosphamide or doxorubicin hydrochloride, cyclophosphamide, and paclitaxel. Trastuzumab is administered in some groups.

1 year

Every 3 weeks for chemotherapy, weekly for paclitaxel, and every 3 weeks for trastuzumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 6 months for 5 years, then annually for 5 years

Treatment Details

Interventions

• Cyclophosphamide
• Docetaxel
• Doxorubicin
• Paclitaxel
• Trastuzumab

Trial Overview The study compares chemotherapy alone versus chemotherapy with trastuzumab (a monoclonal antibody) post-surgery in treating breast cancer. It aims to determine if adding trastuzumab improves outcomes by preventing tumor growth or spread more effectively than chemotherapy alone.

Participant Groups

Group I: Arm II (chemotherapy, trastuzumab) Experimental Treatment 8 Interventions

GROUP IIA: Patients receive docetaxel and cyclophosphamide as in Group IA. Patients also receive trastuzumab IV over 30-90 minutes on day 1. Courses repeat every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity. GROUP IIB: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in Group IB. Patients also receive trastuzumab IV over 30-90 minutes weekly for 12 doses and then every 3 weeks for subsequent doses. Treatment repeats every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (chemotherapy) Active Control 7 Interventions

GROUP IA: Patients receive docetaxel IV over 60 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP IB: Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning 2-3 weeks after last dose of doxorubicin hydrochloride and cyclophosphamide, patients also receive paclitaxel IV over 60 minutes once weekly for 12 doses in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Findings from Research

Doxorubicin combined with docetaxel has shown high effectiveness in treating advanced breast cancer without significantly increasing the risk of congestive heart failure, unlike the combination with paclitaxel.

While the combination of doxorubicin and paclitaxel improved response rates, it did not enhance overall survival, highlighting the need for further evaluation of doxorubicin/docetaxel combinations in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compilation of phase I and II trial data of docetaxel and doxorubicin in the treatment of advanced breast cancer and other malignancies. Sparano, JA.[2018]

The combination of doxorubicin (Dox) and paclitaxel has been established as a superior treatment for metastatic breast cancer, showing better response rates and longer time to disease progression compared to either drug alone, based on a phase III study.

New agents like Herceptin (trastuzumab) and DPPE are being investigated to enhance the efficacy of Dox and paclitaxel, with early results indicating they may improve response rates and prolong disease progression time when used in combination with these chemotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in chemotherapy of advanced breast cancer. Lebwohl, DE., Canetta, R.[2016]

The combination of docetaxel and doxorubicin (TAC) has shown significantly higher response rates in advanced breast cancer treatment compared to traditional regimens, with a response rate of 54% versus 42% for the 5-fluorouracil/doxorubicin/cyclophosphamide regimen, based on a study involving 484 patients.

While TAC treatment was associated with a higher incidence of febrile neutropenia, it did not increase the risk of serious infections or cardiotoxicity, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel in the treatment of breast cancer: an update on recent studies. Nabholtz, JM., Reese, DM., Lindsay, MA., et al.[2019]

Doxorubicin has historically been the most effective treatment for metastatic breast cancer, especially when combined with other agents like 5-fluorouracil and cyclophosphamide, leading to improved patient outcomes.

New agents such as docetaxel have shown significantly higher response rates than doxorubicin in phase III trials, and importantly, docetaxel does not carry the same risk of cardiotoxicity, making it a promising option for combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining new agents with anthracyclines in metastatic breast cancer: an overview of recent findings. Aapro, MS.[2018]

The doxorubicin-docetaxel combination is an effective first-line chemotherapy for metastatic breast cancer, achieving an overall response rate of 67% among 40 assessable patients, with 16% achieving complete remission and 51% partial remission.

The treatment was well-tolerated, with no severe cardiac or neurological toxicity reported, although 58% of patients experienced significant neutropenia, which was managed with G-CSF or GM-CSF support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-survival in responding patients with metastatic breast cancer treated with doxorubicin-docetaxel combination. A multicentre phase II trial. Mattioli, R., Lippe, P., Massacesi, C., et al.[2018]

The combination of docetaxel, doxorubicin, and cyclophosphamide (TAC) shows high efficacy in treating metastatic breast cancer, with response rates reaching up to 80% in preliminary phase II trials.

The TAC regimen is well tolerated, with low rates of cardiac toxicity (only 2% experienced reversible congestive heart failure) despite the high incidence of grade 4 neutropenia in 68% of treatment cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel/doxorubicin/cyclophosphamide in the treatment of metastatic breast cancer. Nabholtz, JM., Smylie, M., Mackey, JR., et al.[2018]

In a review of five phase III clinical trials, docetaxel was associated with a higher incidence of grade 3/4 neutropenia compared to paclitaxel, indicating a distinct safety profile for each taxane.

Paclitaxel was more likely to cause peripheral neuropathy, while docetaxel had higher rates of gastrointestinal adverse events, suggesting that the choice of taxane may depend on the patient's tolerance to these specific side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systemic review of taxanes and their side effects in metastatic breast cancer. Lai, JI., Chao, TC., Liu, CY., et al.[2022]

Docetaxel and doxorubicin combinations (TA or TAC) show high efficacy in treating metastatic breast cancer, with response rates between 70% to 80%, even in patients with visceral metastases.

The main toxicity observed is neutropenia, but significant cardiotoxicity has not been reported, even at high cumulative doses of doxorubicin, indicating a favorable safety profile for these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel and anthracycline polychemotherapy in the treatment of breast cancer. Nabholtz, JM., Smylie, M., Mackey, J., et al.[2018]

A new regimen combining doxorubicin and paclitaxel has been developed that is both well-tolerated and highly effective, utilizing bolus administration of doxorubicin and a 3-hour infusion of paclitaxel, overcoming previous schedule-dependent toxicity issues.

Paclitaxel has shown promising results when combined with fluorouracil and folinic acid in patients with extensive prior chemotherapy, and adding mitoxantrone to this combination appears to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-based combination chemotherapy for breast cancer. Hortobagyi, GN.[2015]

References

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

Compilation of phase I and II trial data of docetaxel and doxorubicin in the treatment of advanced breast cancer and other malignancies. [2018]

2. England pubmed.ncbi.nlm.nih.gov

New developments in chemotherapy of advanced breast cancer. [2016]

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

Docetaxel in the treatment of breast cancer: an update on recent studies. [2019]

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

Combining new agents with anthracyclines in metastatic breast cancer: an overview of recent findings. [2018]

5. Greece pubmed.ncbi.nlm.nih.gov

Long-survival in responding patients with metastatic breast cancer treated with doxorubicin-docetaxel combination. A multicentre phase II trial. [2018]

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

Docetaxel/doxorubicin/cyclophosphamide in the treatment of metastatic breast cancer. [2018]

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

Docetaxel/anthracycline combinations for breast cancer treatment. [2019]

8. Switzerland pubmed.ncbi.nlm.nih.gov

A systemic review of taxanes and their side effects in metastatic breast cancer. [2022]

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

Docetaxel and anthracycline polychemotherapy in the treatment of breast cancer. [2018]

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

The cardioprotective role of probucol against anthracycline and trastuzumab-mediated cardiotoxicity. [2016]

11. Japan pubmed.ncbi.nlm.nih.gov

[Two cases treated with trastuzumab as primary chemotherapy]. [2015]

12. Greece pubmed.ncbi.nlm.nih.gov

Which sequence best protects the heart against trastuzumab and anthracycline toxicity? An electron microscopy study in rats. [2015]

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

Paclitaxel-based combination chemotherapy for breast cancer. [2015]