Chemotherapy +/− Bevacizumab for Breast Cancer

Recruiting at 928 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anthracyclines, Anthracenediones, Taxanes

Disqualifiers: HER2+ cancer, Cardiovascular disease, 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: 5

Duration: 20-24 weeks

4994 Participants Needed

Trial Summary

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

The trial does not specify if you need to stop taking your current medications. However, if you are taking tamoxifen or raloxifene, you must stop them before starting the trial.

What data supports the effectiveness of the drug combination including Bevacizumab, Paclitaxel, and Doxorubicin for breast cancer?

Research shows that Paclitaxel, when combined with Doxorubicin, has a high response rate in treating breast cancer, with significant tumor shrinkage and improved survival rates. Additionally, Paclitaxel has been effective in both early and advanced stages of breast cancer, especially when used in combination with other drugs like Cyclophosphamide. ^{1 2 3 4 5}

Is the combination of chemotherapy drugs like Paclitaxel and Doxorubicin safe for breast cancer treatment?

Paclitaxel and Doxorubicin, used in breast cancer treatment, can cause side effects like hypersensitivity reactions, nerve damage, and heart issues. However, studies show that with careful dosing, these side effects can be managed, and the combination is generally considered safe for patients. ^{6 7 8 9 10}

What makes the chemotherapy treatment with Bevacizumab unique for breast cancer?

This treatment combines chemotherapy drugs with Bevacizumab, a drug that targets blood vessels to stop them from feeding the cancer, which may enhance the effectiveness of the chemotherapy. This combination is particularly noted for its potential in treating advanced breast cancer that does not overexpress HER2, offering a different approach compared to standard chemotherapy alone. ^{11 12 13 14 15}

What is the purpose of this trial?

This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, and paclitaxel to see how well they work with or without bevacizumab in treating patients with cancer that has spread to the lymph nodes (lymph node-positive) or cancer that has not spread to the lymph nodes but is at high risk for returning (high-risk, lymph node-negative breast cancer). Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, and paclitaxel, 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. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery and help prevent the tumor from returning. It is not yet known whether doxorubicin hydrochloride, cyclophosphamide, and paclitaxel are more effective with or without bevacizumab.

Research Team

Kathy D Miller

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults with breast cancer that has spread to lymph nodes or is at high risk of returning. They must have had surgery between 28-84 days before starting treatment, be in good physical condition (ECOG 0-1), and have normal blood counts and organ function tests. People with HER2+ breast cancer, recent major surgeries, uncontrolled heart conditions, bleeding disorders, or who are pregnant can't join.

Inclusion Criteria

My breast cancer is not HER2 positive as determined by specific tests.

I have cancer in both breasts, but the more advanced one qualifies for the trial.

I have had a heart attack in the last 12 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel with or without bevacizumab

20-24 weeks

Every 2 or 3 weeks for 4 courses, then every 3 weeks for 4 courses

Extended Treatment

Participants in Arm III receive additional bevacizumab monotherapy

30 weeks

Every 3 weeks for 10 courses

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Treatment Details

Interventions

• Bevacizumab
• Cyclophosphamide
• Doxorubicin Hydrochloride
• Paclitaxel

Trial Overview The study compares the effectiveness of chemotherapy drugs doxorubicin hydrochloride, cyclophosphamide, and paclitaxel with or without the antibody bevacizumab in patients after surgery. Bevacizumab may block tumor blood supply. The goal is to see which combination better prevents cancer from coming back.

Participant Groups

Group I: Arm III (chemotherapy, bevacizumab monotherapy) Experimental Treatment 6 Interventions

Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.

Group II: Arm II (chemotherapy, bevacizumab) Experimental Treatment 6 Interventions

Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.

Group III: Arm I (chemotherapy, placebo) Active Control 6 Interventions

Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.

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+

Cancer and Leukemia Group B

Collaborator

Trials

81

Recruited

118,000+

Eastern Cooperative Oncology Group

Collaborator

Trials

272

Recruited

153,000+

North Central Cancer Treatment Group

Collaborator

Trials

49

Recruited

81,100+

Findings from Research

Paclitaxel, when combined with doxorubicin, has shown a remarkable 95% objective response rate in chemotherapy-naive patients with metastatic breast cancer, indicating its high efficacy in treating this condition.

The treatment regimen demonstrated no signs of cardiac toxicity, allowing for further testing in patients with smaller tumors to potentially increase the rate of complete remission before surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future developments for paclitaxel in the treatment of breast cancer. Bonadonna, G.[2015]

In two large randomized trials, adding intravenous paclitaxel to standard doxorubicin-cyclophosphamide (AC) therapy significantly improved disease-free survival at 5 years for women with early breast cancer, with one trial also showing improved overall survival.

While paclitaxel demonstrated efficacy in neoadjuvant therapy by increasing response rates and eligibility for breast-conserving surgery, it was associated with notable grade 3-4 adverse events, primarily hematological issues like neutropenia and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel: as adjuvant or neoadjuvant therapy in early breast cancer. Simpson, D., Plosker, GL.[2018]

Paclitaxel (Taxol) is a significant new chemotherapy drug for breast cancer, showing promise in both single-agent and combination treatments.

Ongoing research at Memorial Sloan-Kettering Cancer Center aims to optimize the use of paclitaxel in various treatment settings, including metastatic and adjuvant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memorial Sloan-Kettering Cancer Center experience with paclitaxel in the treatment of breast cancer. Seidman, AD., Hudis, CA., Fennelly, D., et al.[2015]

Paclitaxel (Taxol) is an effective chemotherapy agent for treating ovarian cancer and metastatic breast cancer, particularly in patients who have not responded to platinum-based treatments.

Nurses must be aware of the potential side effects of Paclitaxel, such as hypersensitivity reactions and peripheral neuropathy, and follow specific administration guidelines to avoid complications related to its interaction with PVC intravenous-giving sets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel (Taxol)--a guide to administration. Preston, NJ.[2019]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

In a case series of 15 patients with metastatic non-squamous cell lung carcinoma, the combination of paclitaxel and bevacizumab showed a partial response rate of 44% based on CT scans and 65% based on PET scans, indicating potential efficacy in this patient population.

No major toxicity was observed in the treatment, and the median progression-free survival was 4.6 months, suggesting that this regimen is safe and may improve patient outcomes, warranting further investigation in a randomized clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of paclitaxel and bevacizumab in heavily pre-treated non-small-cell lung cancer (NSCLC) patients: a case series study on 15 patients. Le Moulec, S., Hadoux, J., Gontier, E., et al.[2015]

Standard treatments for breast cancer after initial chemotherapy include capecitabine, S-1, vinorelbine, irinotecan, or gemcitabine, which are effective options for managing the disease.

Newer therapies like lapatinib for trastuzumab-resistant cases and combinations like bevacizumab with taxanes show promise, highlighting the need for further research on optimal drug sequences and combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy for breast cancer refractory to anthracycline, taxane or trastuzumab]. Ito, Y., Kobayashi, K.[2016]

A case study of a 39-year-old woman with recurrent breast cancer treated with bevacizumab and paclitaxel revealed a serious side effect: diverticular bleeding after the third treatment cycle.

The report suggests that bevacizumab may contribute to diverticular bleeding, highlighting the importance of assessing patient history for risk factors like diverticulitis and prior abdominal surgeries before starting this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diverticular Bleeding of the Colon during Combination Chemotherapy with Bevacizumab and Paclitaxel for Recurrent Breast Cancer. Nakayama, Y., Ito, Y., Tanabe, M., et al.[2021]

References

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

The efficacy and safety of preoperative chemotherapy with triweekly abraxane and cyclophosphamide followed by 5-Fluorouracil, epirubicin, and cyclophosphamide therapy for resectable breast cancer: a multicenter clinical trial. [2015]

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

Future developments for paclitaxel in the treatment of breast cancer. [2015]

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

Paclitaxel: as adjuvant or neoadjuvant therapy in early breast cancer. [2018]

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

Memorial Sloan-Kettering Cancer Center experience with paclitaxel in the treatment of breast cancer. [2015]

5. Hungary pubmed.ncbi.nlm.nih.gov

[Chemotherapy of breast cancer: focus on paclitaxel] [2019]

6. England pubmed.ncbi.nlm.nih.gov

Paclitaxel (Taxol)--a guide to administration. [2019]

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

Prospective assessment of cardiac toxicity during a randomized phase II trial of doxorubicin and paclitaxel in metastatic breast cancer. [2015]

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

Nursing management of the patient receiving Taxol therapy. [2015]

9. Egypt pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]

10. Greece pubmed.ncbi.nlm.nih.gov

Weekly pegylated liposomal doxorubicin and paclitaxel in patients with metastatic breast carcinoma: A phase II study. [2021]

11. Greece pubmed.ncbi.nlm.nih.gov

Bevacizumab as First-line Treatment for HER2-negative Advanced Breast Cancer: Paclitaxel plus Bevacizumab Versus Other Chemotherapy. [2021]

12. France pubmed.ncbi.nlm.nih.gov

Combination of paclitaxel and bevacizumab in heavily pre-treated non-small-cell lung cancer (NSCLC) patients: a case series study on 15 patients. [2015]

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

Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. [2023]

14. Japan pubmed.ncbi.nlm.nih.gov

[Chemotherapy for breast cancer refractory to anthracycline, taxane or trastuzumab]. [2016]

15. Switzerland pubmed.ncbi.nlm.nih.gov

Diverticular Bleeding of the Colon during Combination Chemotherapy with Bevacizumab and Paclitaxel for Recurrent Breast Cancer. [2021]