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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three medicines—durvalumab (an immunotherapy drug), trastuzumab, and pertuzumab—to determine their safety and effectiveness in treating HER2-enriched breast cancer. The focus is on women whose cancer tests positive for high levels of the HER2 protein, which can accelerate cancer growth. Women with tumors larger than 1 cm and without hormone-driven cancer might be suitable for this study. Participants will receive the three drugs every three weeks for six cycles and must attend regular visits and tests. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of durvalumab, trastuzumab, and pertuzumab is under study for safety in treating HER2-enriched breast cancer. Previous studies have found that patients generally tolerate this combination well. Common side effects include tiredness, nausea, and diarrhea, but these are usually mild to moderate.

The FDA has already approved trastuzumab and pertuzumab for other breast cancer treatments, supporting their known safety. Durvalumab has been tested with other treatments, and results suggest it is also well-tolerated. Overall, while side effects can occur, most patients find them manageable. Prospective trial participants should discuss any concerns with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Durvalumab, Trastuzumab, and Pertuzumab for breast cancer because it brings together three powerful agents that target cancer cells in different ways. Trastuzumab and Pertuzumab are known for their ability to target HER2-positive cancer cells, a common characteristic in aggressive breast cancers. The addition of Durvalumab, an immune checkpoint inhibitor, is particularly promising as it can enhance the body’s immune response against cancer cells, potentially leading to better outcomes. This unique combination could offer a more comprehensive attack against cancer by not only targeting cancer cells directly but also boosting the immune system’s ability to fight the disease.

What evidence suggests that this trial's treatments could be effective for HER2-enriched breast cancer?

This trial will evaluate the combination of durvalumab, trastuzumab, and pertuzumab for treating HER2-enriched breast cancer. Studies have shown promising results for using these three drugs together. Durvalumab helps the immune system attack cancer cells, while trastuzumab and pertuzumab target the HER2 protein, often found in high amounts in this type of breast cancer. Research indicates that this combination can lead to a higher rate of complete response, meaning no cancer is detectable after treatment. Early trials demonstrated that using these drugs together can be more effective than using them separately. This suggests that the combination treatment could be a strong option for treating HER2-positive breast cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Polly Niravath, M.D.

Principal Investigator

Houston Methodist Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

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