Durvalumab + Chemotherapy for Breast Cancer

Recruiting at 471 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Live vaccines

Disqualifiers: Metastatic disease, Active autoimmune, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase III trial compares the addition of an immunotherapy drug (durvalumab) to usual chemotherapy versus usual chemotherapy alone in treating patients with MammaPrint Ultrahigh (MP2) stage II-III hormone receptor positive, HER2 negative breast cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as paclitaxel, doxorubicin, and cyclophosphamide 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. There is some evidence from previous clinical trials that people who have a MammaPrint Ultrahigh Risk result may be more likely to respond to chemotherapy and immunotherapy. Adding durvalumab to usual chemotherapy may be able to prevent the cancer from returning for patients with MP2 stage II-III hormone receptor positive, HER2 negative breast cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot receive any other cancer treatments like chemotherapy, immunotherapy, or hormonal therapy while participating in this study.

What evidence supports the effectiveness of the drug combination of Durvalumab, Doxorubicin, and Paclitaxel for breast cancer?

Research shows that the combination of Doxorubicin and Paclitaxel is highly effective for treating advanced breast cancer, with high response rates and manageable side effects. This combination is considered a standard treatment for metastatic breast cancer, suggesting its potential effectiveness when combined with Durvalumab. ^{1 2 3 4 5}

Is the combination of Durvalumab, Doxorubicin, Cyclophosphamide, and Paclitaxel safe for humans?

The combination of Doxorubicin and Paclitaxel has been studied for breast cancer and is known to be effective, but it can cause heart-related side effects. Limiting the dose of Doxorubicin and using additional medications can help reduce these risks. Cyclophosphamide is also commonly used in cancer treatment, but specific safety data for the combination with Durvalumab is not detailed in the provided studies. ^{2 6 7 8 9}

What makes the drug combination of Durvalumab, Cyclophosphamide, Doxorubicin, and Paclitaxel unique for breast cancer treatment?

This drug combination is unique because it includes Durvalumab, an immunotherapy drug that helps the immune system attack cancer cells, alongside traditional chemotherapy drugs like Doxorubicin and Paclitaxel, which are known to be effective in treating advanced breast cancer. The addition of Durvalumab may enhance the overall effectiveness of the treatment by combining immune system activation with chemotherapy. ^{1 2 4 10 11}

Research Team

Erin F Cobain

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with stage II-III hormone receptor positive, HER2 negative breast cancer who have not had prior treatment. They must be in good physical condition (Zubrod Performance Status of 0-2), have no metastatic disease, and cannot be pregnant or breastfeeding. Participants need to agree to use effective contraception and should not have a history of certain conditions like uncontrolled diabetes, active pneumonitis, or autoimmune diseases requiring recent systemic treatment.

Inclusion Criteria

As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

My breast cancer has not come back in the same area after treatment.

Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

MammaPrint Testing

Patients without a known MammaPrint Ultrahigh (MP2) score undergo MammaPrint testing on a previously-collected tissue sample

1-2 weeks

1 visit (in-person)

Treatment

Patients receive neoadjuvant chemotherapy with or without durvalumab. Paclitaxel is administered every 14 days for 6 cycles, followed by doxorubicin and cyclophosphamide every 14 days for 4 cycles.

20 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Treatment Details

Interventions

• Cyclophosphamide (Chemotherapy)
• Doxorubicin (Chemotherapy)
• Durvalumab (Checkpoint Inhibitor)
• Paclitaxel (Chemotherapy)

Trial Overview The study tests if adding Durvalumab (an immunotherapy drug) to standard chemotherapy (Paclitaxel, Cyclophosphamide, Doxorubicin) improves outcomes for patients with specific high-risk breast cancer as identified by MammaPrint testing. It's a phase III trial where participants are randomly assigned to receive either the new combination therapy or just the usual chemotherapy.

Participant Groups

Group I: Step 2, Arm 2 (chemotherapy, durvalumab) Experimental Treatment 7 Interventions

Patients receive paclitaxel IV over 30-60 minutes on days 1 and 8 of each cycle and durvalumab IV over 60 minutes on day 1 of every other cycle. Treatment repeats every 14 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1 of each cycle, and durvalumab IV over 60 minutes on day 1 of every other cycle. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo mammography during screening (STEP 1). Patients have the option to also undergo collection of tumor tissue during initial biopsy (STEP 1) and at SOC surgery, and undergo collection of blood samples prior to STEP 2 treatment, after cycle one of chemotherapy, and one month post-SOC surgery.

Group II: Step 1 (MammaPrint testing) Experimental Treatment 1 Intervention

Patients without a known MP2 score undergo MammaPrint testing on a previously-collected tissue sample. Patients with MP2 score proceed to STEP 2.

Group III: Step 2, Arm 1 (chemotherapy) Active Control 6 Interventions

Patients receive paclitaxel IV over 30-60 minutes on days 1 and 8 of each cycle. Treatment repeats every 14 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1 of each cycle. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo mammography during screening (STEP 1). Patients have the option to also undergo collection of tumor tissue during initial biopsy (STEP 1) and at SOC surgery, and undergo collection of blood samples prior to STEP 2 treatment, after cycle one of chemotherapy, and one month post-SOC surgery.

Cyclophosphamide is already approved in Canada, Japan for the following indications:

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+

Findings from Research

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 intravenous paclitaxel and bolus doxorubicin is an effective primary chemotherapy for stage IV breast cancer, showing significant activity with manageable side effects.

Limiting the total dose of doxorubicin to 360 mg/m2 and using granulocyte colony-stimulating factor can reduce the risk of cardiotoxicity and neutropenia, while continuing treatment with paclitaxel can enhance the chances of a complete response in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience at the Istituto Nazionale Tumori with paclitaxel in combination with doxorubicin in women with untreated breast cancer. Gianni, L., Capri, G.[2015]

The combination therapy of doxorubicin and paclitaxel (AT) showed a superior overall response rate (47%) and longer median time to treatment failure (8.0 months) compared to single-agent therapies, although the difference in survival rates was not significant.

Both doxorubicin and paclitaxel demonstrated equivalent efficacy, with median survivals of 18.9 months for doxorubicin and 22.2 months for paclitaxel, indicating that while combination therapy may enhance response rates, it does not necessarily lead to improved survival or quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). Sledge, GW., Neuberg, D., Bernardo, P., et al.[2022]

The combination of Doxil (40 mg/m2) and vinorelbine (30 mg/m2) was found to be effective in treating metastatic breast cancer in a phase I study involving 30 women, with a recommended schedule for further testing.

This combination therapy demonstrated a favorable toxicity profile, with minimal severe side effects like neutropenia and a low incidence of significant nausea, vomiting, or hair loss, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. Burstein, HJ., Ramirez, MJ., Petros, WP., et al.[2020]

Combining paclitaxel with doxorubicin has shown impressive remission rates for metastatic breast cancer, with overall rates exceeding 90% and nearly 50% achieving complete remission, especially when administered in a specific sequence.

While other combinations of paclitaxel with drugs like cisplatin and vinorelbine have shown variable results, the doxorubicin/paclitaxel combination remains the most effective and tolerable treatment option currently available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-containing combination chemotherapy for metastatic breast cancer. Hortobagyi, GN., Ibrahim, N.[2018]

Doxorubicin (DOX) is an effective chemotherapy drug for breast cancer that works by damaging DNA and inducing apoptosis, but it has a risk of cardiotoxicity, limiting the total dose patients can receive.

The PEGylated liposomal formulation of DOX (L-DOX), known as Doxil® or Caelyx®, has been developed to improve cardiovascular safety and increase circulation time, although it is not yet FDA approved for metastatic breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. Franco, YL., Vaidya, TR., Ait-Oudhia, S.[2020]

In a study involving male rats treated with doxorubicin (DOX) and paclitaxel (PTX), the addition of dexrazoxane (DZR) significantly reduced the cardiotoxic effects of DOX, demonstrating its cardioprotective properties.

The combination of DOX and PTX did not worsen the heart damage caused by DOX alone, and DZR maintained its protective effects without increasing noncardiac toxicity, suggesting a safer treatment regimen for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. Della Torre, P., Imondi, AR., Bernardi, C., et al.[2015]

In a study of 47 elderly women with high-risk breast cancer, the combination of Non-Pegylated Liposomal Doxorubicin (NPL-DOX) and Cyclophosphamide followed by weekly Paclitaxel showed a low rate of cardiac toxicity over a median follow-up of 76 months, with only one case of grade 3 congestive heart failure reported.

While there was a gradual decline in left ventricular ejection fraction (LVEF) over time, it remained above 50% and did not lead to any significant clinical symptoms, indicating that the treatment is relatively safe for cardiac health in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study. Coltelli, L., Finale, C., Musettini, G., et al.[2023]

The combination of paclitaxel and doxorubicin has significantly improved clinical outcomes for breast cancer patients, particularly in neoadjuvant settings for locally advanced cases.

However, this combination therapy is associated with cardiac toxicity, highlighting the need for careful monitoring and future research to mitigate these risks while maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cardiac tolerance of the combination paclitaxel-anthracyclines in the context of the management of cancer of the breast]. Ferrero, JM., Magné, N., Foa, C., et al.[2015]

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]

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]

References

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

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

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

Experience at the Istituto Nazionale Tumori with paclitaxel in combination with doxorubicin in women with untreated breast cancer. [2015]

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

Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). [2022]

4. England pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. [2020]

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

Paclitaxel-containing combination chemotherapy for metastatic breast cancer. [2018]

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

Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. [2020]

7. Germany pubmed.ncbi.nlm.nih.gov

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. [2015]

8. Italy pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study. [2023]

9. France pubmed.ncbi.nlm.nih.gov

[Cardiac tolerance of the combination paclitaxel-anthracyclines in the context of the management of cancer of the breast]. [2015]

10. 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]

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

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