Durvalumab + Trastuzumab + Pertuzumab for Breast Cancer

(DTP Trial)

Overseen By Houston Methodist Cancer Center

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: The Methodist Hospital Research Institute

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Autoimmune disorders, Active infection, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 6

Duration: 18 weeks

39 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to test the safety and effectiveness of using durvalumab with trastuzumab and pertuzumab in participants with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot take concurrent chemotherapy, radiation therapy, immunotherapy, or biologic therapy for cancer treatment, and you must not use immunosuppressive medication within 14 days before starting the study treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take any chemotherapy, radiation, immunotherapy, or biologic therapy for cancer treatment while participating. Also, you should not use immunosuppressive medication within 14 days before starting the study treatment.

What data supports the idea that Durvalumab + Trastuzumab + Pertuzumab for Breast Cancer is an effective drug?

The available research shows that combining pertuzumab with trastuzumab and chemotherapy improves survival in HER2-positive early and metastatic breast cancer. Specifically, the CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab and docetaxel significantly increased the time patients lived without their cancer getting worse, as well as their overall survival, compared to using trastuzumab and docetaxel alone. This suggests that the combination of these drugs is effective for treating HER2-positive breast cancer. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Durvalumab, Trastuzumab, and Pertuzumab for breast cancer?

Research shows that combining pertuzumab with trastuzumab and chemotherapy improves survival in HER2-positive breast cancer. Additionally, durvalumab has shown effectiveness in enhancing immune responses against cancer cells in various solid tumors. ^{1 2 3 4 5}

What safety data is available for the combination of Durvalumab, Trastuzumab, and Pertuzumab in breast cancer treatment?

The safety data for the combination of Durvalumab, Trastuzumab, and Pertuzumab in breast cancer treatment can be inferred from several studies. Pertuzumab has been evaluated for safety in HER2-positive breast cancer, with its adverse events monitored through the FDA Adverse Event Reporting System (FAERS). Trastuzumab has been studied in combination with other agents like trastuzumab emtansine (T-DM1) and pertuzumab, with safety characterized in phase IIa trials. Additionally, a phase Ib trial assessed the safety of Durvalumab in combination with Trastuzumab in HER2-positive metastatic breast cancer. These studies collectively provide insights into the safety profile of these drugs when used in combination for breast cancer treatment. ^{6 7 8 9 10}

Is the combination of Durvalumab, Trastuzumab, and Pertuzumab safe for humans?

The combination of these drugs has been studied in various settings, and while they have shown effectiveness in treating HER2-positive breast cancer, their safety is continuously monitored. Pertuzumab, for example, is widely used but requires ongoing safety evaluations due to potential adverse events. Durvalumab and Trastuzumab have been studied together in trials, indicating that they are generally safe, but as with any treatment, monitoring for side effects is important. ^{6 7 8 9 10}

Is the drug combination of Durvalumab, Pertuzumab, and Trastuzumab promising for breast cancer?

Yes, the combination of Pertuzumab and Trastuzumab is promising for treating HER2-positive breast cancer. Pertuzumab and Trastuzumab work well together to stop cancer cells from growing and spreading. Studies have shown that this combination can improve survival rates and reduce tumor size in patients with this type of breast cancer. ^{5 11 12 13 14}

What makes the drug combination of Durvalumab, Trastuzumab, and Pertuzumab unique for breast cancer treatment?

This drug combination is unique because it combines Durvalumab, an immune checkpoint inhibitor, with Trastuzumab and Pertuzumab, which are both HER2-targeting antibodies. This combination aims to enhance the immune system's ability to fight cancer while simultaneously blocking HER2 receptors, which are often overexpressed in certain breast cancers, potentially offering a more comprehensive approach to treatment. ^{5 11 12 13 14}

Research Team

Polly Niravath, M.D.

Principal Investigator

Houston Methodist Cancer Center

Eligibility Criteria

This trial is for postmenopausal or non-pregnant premenopausal women over 18 with HER2-enriched and amplified breast cancer. Participants must have good heart function, organ and marrow health, and be able to follow the study protocol. Those with severe heart issues, recent major surgery, other treatments for cancer, autoimmune diseases, infections like TB or HIV, or on immunosuppressants can't join.

Inclusion Criteria

I am a woman over 18 years old.

My heart pumps well, with an ejection fraction of 50% or more.

My organs and bone marrow are working well.

Exclusion Criteria

Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients

You have had an organ transplant from another person.

I haven't taken immunosuppressive drugs in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Durvalumab, trastuzumab, and pertuzumab are administered on Day 1 every 3 weeks for 6 cycles

18 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Determination of 3-year disease-free survival (DFS) rate in patients who achieve pCR

3 years

Treatment Details

Interventions

• Durvalumab
• Pertuzumab
• Trastuzumab

Trial Overview The trial tests the safety and effectiveness of combining durvalumab with trastuzumab and pertuzumab in treating HER2-enriched breast cancer. It aims to see how well these drugs work together against this specific type of breast cancer.

Participant Groups

Group I: Durvalumab + Trastuzumab + Pertuzumab Experimental Treatment 3 Interventions

Durvalumab, trastuzumab, and pertuzumab will be administered on Day 1 every 3 weeks for 6 cycles. Trastuzumab will be administered as 8 mg/kg intravenous (IV) loading dose, followed by 6 mg/kg IV. Pertuzumab will be administered as 840 mg IV loading dose, followed by 420 mg. Durvalumab will be administered at a fixed dose of 1120 mg IV.

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

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

The combination of MEDI0680 and durvalumab was found to be safe and tolerable in patients with advanced clear-cell renal cell carcinoma, but it did not show improved efficacy compared to nivolumab alone, with objective response rates of 16.7% for the combination and 23.8% for nivolumab.

Both treatment groups had a median progression-free survival of 3.6 months, and a notable percentage of patients (23.8% in the combination group) discontinued treatment due to adverse events, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. Voss, MH., Azad, AA., Hansen, AR., et al.[2023]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In a phase 3 trial involving 780 patients with HER2-positive metastatic gastric or gastro-oesophageal junction cancer, adding pertuzumab to trastuzumab and chemotherapy did not significantly improve overall survival compared to placebo, with median survival times of 17.5 months for the pertuzumab group and 14.2 months for the control group.

While serious adverse events were more common in the pertuzumab group (45%) compared to the control group (39%), no treatment-related deaths occurred in the pertuzumab group, suggesting a safety profile that warrants further investigation despite the lack of survival benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Tabernero, J., Hoff, PM., Shen, L., et al.[2023]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Pertuzumab is an effective anti-HER2 monoclonal antibody that works by preventing HER2 from forming heterodimers, which reduces tumor cell growth and survival, particularly in HER2-positive metastatic breast cancer.

In the phase III CLEOPATRA trial involving a combination of pertuzumab, trastuzumab, and docetaxel, patients experienced significantly improved progression-free survival and overall survival compared to those receiving placebo, with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer. McCormack, PL.[2021]

A comprehensive analysis of 14,707 adverse events related to pertuzumab from the FDA Adverse Event Reporting System revealed significant safety concerns, including potential risks of myelosuppression, cardiotoxicity, and other serious conditions occurring in 12 organ systems.

Most adverse events, particularly cardiac-related issues, were reported within the first month of therapy, highlighting the need for careful monitoring and preparedness for emergency interventions, especially in elderly patients and those with pre-existing cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A disproportionality analysis of adverse events associated to pertuzumab in the FDA Adverse Event Reporting System (FAERS). Zou, SP., Yang, HY., Ouyang, ML., et al.[2023]

In a study of 266 patients with HER2-positive metastatic breast cancer, the majority received a treatment regimen of trastuzumab, pertuzumab, and a taxane, which aligns with the standard first-line therapy.

The median progression-free survival (PFS) for patients was 16.9 months, and the safety profile, including common side effects like fatigue and diarrhea, was consistent with findings from the pivotal CLEOPATRA trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HER2-Positive Metastatic Breast Cancer Patients Receiving Pertuzumab in a Community Oncology Practice Setting: Treatment Patterns and Outcomes. Robert, NJ., Goertz, HP., Chopra, P., et al.[2020]

In a phase IIa study involving 64 patients with HER2-positive metastatic breast cancer, the combination of trastuzumab emtansine (T-DM1) and pertuzumab showed an overall objective response rate (ORR) of 41%, with a higher ORR of 57% in first-line patients, indicating promising efficacy for this treatment.

The combination therapy was generally safe, with common side effects including fatigue (61%) and nausea (50%), and no unexpected toxicities were reported, suggesting that this treatment can be administered at full doses without significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. Miller, KD., Diéras, V., Harbeck, N., et al.[2022]

Pertuzumab, a new monoclonal antibody targeting HER2, has shown improved patient outcomes in clinical trials for early-stage and metastatic HER2-positive breast cancer, especially when used in combination with chemotherapy and trastuzumab.

The review highlights that while trastuzumab has improved survival for HER2-positive breast cancer, there is still a need for better treatment options, which pertuzumab aims to address, particularly for patients who continue to relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab in human epidermal growth-factor receptor 2-positive breast cancer: clinical and economic considerations. Lamond, NW., Younis, T.[2021]

In a phase Ib trial involving 15 patients with heavily pretreated HER2-positive metastatic breast cancer, the combination of durvalumab and trastuzumab showed no significant clinical activity, with only 29% of patients achieving stable disease and no responses observed according to RECIST criteria.

The study highlighted the importance of PD-L1 expression as a selection biomarker, as all patients had <1% PD-L1 expression, suggesting that the lack of immune response may be linked to the tumor microenvironment and T-cell exhaustion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229). Chia, S., Bedard, PL., Hilton, J., et al.[2020]

In a study of 55 patients with metastatic HER2-positive breast cancer, the combination of pertuzumab and trastuzumab with locoregional radiotherapy was well tolerated, with only 5.4% experiencing significant skin toxicity and no major gastrointestinal or cardiac side effects.

The treatment showed promising safety, allowing for effective local management of the disease, as indicated by a median follow-up of 4.1 years and a minimal change in heart function after radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab and Trastuzumab Combination with Concomitant Locoregional Radiotherapy for the Treatment of Breast Cancers with HER2 Receptor Overexpression. Aboudaram, A., Loap, P., Loirat, D., et al.[2021]

Pertuzumab is a novel monoclonal antibody that acts as a dimerization inhibitor, recently approved for treating HER2-positive breast cancer, showing significant improvement in overall survival when used with trastuzumab and docetaxel in a large phase III trial.

The drug also enhances the complete pathological response rate in the neoadjuvant setting, and ongoing research is exploring its potential effectiveness in treating other solid tumors beyond breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab: development beyond breast cancer. Barthélémy, P., Leblanc, J., Goldbarg, V., et al.[2016]

The novel anti-HER2 antibody 5G9 showed significantly stronger synergistic effects with trastuzumab in inhibiting cell growth compared to pertuzumab, achieving an 85% inhibition rate versus 55% (P<0.001).

In animal models, the combination of 5G9 and trastuzumab demonstrated greater antitumor efficacy than the pertuzumab and trastuzumab combination, suggesting that 5G9 could be a more effective treatment option for HER2-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity. Ding, X., Gu, W., Zhong, Y., et al.[2021]

Pertuzumab has received accelerated approval from the FDA for use with trastuzumab and docetaxel in treating HER2-positive breast cancer, based on improved pathologic complete response rates in a phase 2 trial.

While pertuzumab shows promise in neoadjuvant treatment, further studies are needed to confirm its impact on long-term outcomes like disease-free survival, which will determine its continued approval.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab in neoadjuvant treatment of HER2-positive early breast cancer. Abraham, J., Stenger, M.[2019]

References

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

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. [2023]

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

Durvalumab: First Global Approval. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. [2023]

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

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

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

Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer. [2021]

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

A disproportionality analysis of adverse events associated to pertuzumab in the FDA Adverse Event Reporting System (FAERS). [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

HER2-Positive Metastatic Breast Cancer Patients Receiving Pertuzumab in a Community Oncology Practice Setting: Treatment Patterns and Outcomes. [2020]

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

Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. [2022]

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

Pertuzumab in human epidermal growth-factor receptor 2-positive breast cancer: clinical and economic considerations. [2021]

10. England pubmed.ncbi.nlm.nih.gov

A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229). [2020]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Pertuzumab and Trastuzumab Combination with Concomitant Locoregional Radiotherapy for the Treatment of Breast Cancers with HER2 Receptor Overexpression. [2021]

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

Pertuzumab: development beyond breast cancer. [2016]

13. Netherlands pubmed.ncbi.nlm.nih.gov

A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity. [2021]

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

Pertuzumab in neoadjuvant treatment of HER2-positive early breast cancer. [2019]