T-DXd Combinations for Breast Cancer

(DB-07 Trial)

Recruiting at 75 trial locations

Overseen By AZ Breast Cancer Study Navigators

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must not be taking: Immune checkpoint inhibitors, Topoisomerase I inhibitors, Tucatinib

Disqualifiers: Cardiovascular disease, ILD/pneumonitis, Infection, others

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

Compensation: Varies

Number of Visits: Unknown

245 Participants Needed

Trial Summary

What is the purpose of this trial?

DESTINY-Breast07 will investigate the safety, tolerability, and anti-tumour activity of trastuzumab deruxtecan (T-DXd) in combination with other anti-cancer agents in patients with HER2-positive Metastatic Breast Cancer

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

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination including Pertuzumab for breast cancer?

Research shows that adding Pertuzumab to Trastuzumab and chemotherapy can improve survival rates in patients with HER2-positive breast cancer. In a study, this combination increased the median progression-free survival by 6 months and improved overall survival rates by 10% to 15% compared to those not receiving Pertuzumab. ^{1 2 3 4 5}

What safety data exists for T-DXd combinations in breast cancer treatment?

Pertuzumab, when added to trastuzumab and docetaxel, has been shown to increase survival in breast cancer patients without worsening heart-related side effects, but it may cause severe diarrhea, skin issues, and fever with low white blood cell count. Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in patients with HER2-positive metastatic breast cancer, but specific safety data from the provided research is not detailed. ^{1 2 3 6 7}

What makes the drug T-DXd unique for breast cancer treatment?

T-DXd is unique because it is an antibody-drug conjugate (a targeted cancer therapy) that combines a HER2-targeting antibody with a chemotherapy drug, making it effective for patients with HER2-low breast cancer, who have limited treatment options. ^{8 9 10 11 12}

Eligibility Criteria

This trial is for adults with HER2-positive metastatic breast cancer that's advanced or can't be surgically removed. Participants must have a performance status indicating they are fully active or restricted in physically strenuous activity but ambulatory. They should not have had certain prior treatments, need to have progressed after their last systemic therapy, and may only have stable brain metastases or none at all.

Inclusion Criteria

I have received at least one treatment for my cancer after it spread.

I have brain metastases that haven't been treated or have worsened after treatment.

My cancer cannot be removed by surgery and has spread.

Exclusion Criteria

I have been treated with tucatinib before.

I have no serious lung illnesses besides my cancer.

I have been treated with drugs that boost the immune system.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-finding

Part 1 of each module involves dose-finding to determine the recommended Phase 2 dose (RP2D) of T-DXd in combination with other anti-cancer agents

Variable, up to 53 months

Dose-expansion

Part 2 of each module involves dose-expansion using the RP2D determined in Part 1 to assess safety, tolerability, and anti-tumour activity

Variable, up to 53 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 53 months

Treatment Details

Interventions

• Durvalumab
• Pertuzumab
• Trastuzumab deruxtecan
• Tucatinib

Trial Overview DESTINY-Breast07 explores the effectiveness of trastuzumab deruxtecan (T-DXd) combined with other anti-cancer drugs like Tucatinib, Durvalumab, Paclitaxel, and Pertuzumab in treating HER2-positive metastatic breast cancer. The study aims to assess safety and how well tumors respond to these combinations.

Participant Groups

Group I: Module 7 - T-DXd Experimental Treatment 1 Intervention

T-DXd monotherapy in patients with active brain metastases (Part 2 Only)

Group II: Module 6 - T-DXd and Tucatinib Experimental Treatment 2 Interventions

T-DXd and tucatinib in patients with active brain metastases (Part 2 Only) (Arm not initiated)

Group III: Module 5 - T-DXd and Tucatanib Experimental Treatment 2 Interventions

T-DXd and tucatinib (Arm not initiated in Part 2)

Group IV: Module 4- T-DXd and Durvalumab and Paclitaxel Experimental Treatment 3 Interventions

T-DXd and Durvalumab and Paclitaxel (Arm not initiated in Part 1 and Part 2)

Group V: Module 3- T-DXd and Paclitaxel Experimental Treatment 2 Interventions

T-DXd and Paclitaxel (Arm not initiated in Part 2)

Group VI: Module 2- T-DXd and Pertuzumab Experimental Treatment 2 Interventions

T-DXd and Pertuzumab

Group VII: Module 1- T-DXd and Durvalumab Experimental Treatment 2 Interventions

T-DXd and Durvalumab

Group VIII: Module 0- T-DXd Experimental Treatment 1 Intervention

T-DXd

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

Approved in European Union as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in United States as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in Canada as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Approved in Japan as Perjeta for:

• Early breast cancer
• Metastatic breast cancer

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

Daiichi Sankyo Company, Limited

Collaborator

Trials

2

Recruited

380+

Findings from Research

A study involving 808 patients with HER-2 positive breast cancer showed that adding pertuzumab to trastuzumab and docetaxel significantly improved overall survival, with a 3-year survival rate increase of 10% to 15%.

While pertuzumab did not worsen cardiac toxicity in patients with low cardiovascular risk, it was associated with increased side effects such as severe diarrhea and skin disorders, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

Pertuzumab, a monoclonal antibody targeting HER2, significantly improves progression-free survival in patients with HER2-positive metastatic breast cancer, with a median of 18.5 months compared to 12.4 months for the placebo group, based on a phase III trial with previously untreated patients.

While the overall safety profile of pertuzumab is similar to placebo, it is associated with a higher incidence of specific side effects such as diarrhea, rash, and neutropenia, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Pertuzumab for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer: summary of the scientific assessment of the committee for medicinal products for human use. Boix-Perales, H., Borregaard, J., Jensen, KB., et al.[2023]

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]

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 the DESTINY-Breast01 trial with 184 patients, trastuzumab deruxtecan (T-DXd) showed a confirmed objective response rate of 62.0% and a median overall survival of 29.1 months, indicating its effectiveness in treating HER2-positive metastatic breast cancer after previous treatment with trastuzumab emtansine.

While T-DXd demonstrated sustained antitumor activity, it also had a notable safety profile, with 99.5% of patients experiencing drug-related adverse events, including a 15.8% incidence of interstitial lung disease/pneumonitis, highlighting the importance of monitoring for serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated Patients With HER2-Positive Metastatic Breast Cancer: Updated Survival Results From a Phase 2 Trial (DESTINY-Breast01). Saura, C., Modi, S., Krop, I., et al.[2023]

Trastuzumab deruxtecan (T-DXd) showed promising antitumor activity in patients with advanced HER2-low breast cancer, achieving a 37% objective response rate in a study of 54 patients who had undergone a median of 7.5 prior therapies.

While T-DXd demonstrated efficacy, it also presented significant safety concerns, with 98% of patients experiencing treatment-emergent adverse events, including severe cases of interstitial lung disease (ILD) that led to fatalities, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. Modi, S., Park, H., Murthy, RK., et al.[2021]

Trastuzumab deruxtecan (T-DXd) is a promising new antibody-drug conjugate that has been approved for treating HER2-positive metastatic breast cancer and gastric cancer, showing potential for use in other solid tumors as well.

T-DXd is expected to become the standard second-line treatment for HER2-positive metastatic breast cancer and may also benefit patients with hormone receptor-positive and triple-negative breast cancer that express low levels of HER2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. Perez, J., Garrigós, L., Gion, M., et al.[2022]

Trastuzumab deruxtecan (T-DXd) is effective for breast cancer patients with low ERBB2 positivity (IHC scores of 1+ or 2+), but current standard assays show poor accuracy in distinguishing between low scores (0 and 1+), which could misassign patients for treatment.

In a study involving 18 pathologists assessing 170 breast cancer biopsies, there was only 26% concordance in scoring between 0 and 1+, indicating significant variability in ERBB2 IHC scoring that may impact patient eligibility for T-DXd.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. Fernandez, AI., Liu, M., Bellizzi, A., et al.[2023]

Trastuzumab deruxtecan (T-DXd) has shown significant antitumor activity in patients with HER2-positive advanced gastric cancer (AGC) who have previously undergone at least two therapies, leading to its approval in Japan and by the US FDA.

The treatment resulted in a higher objective response rate and longer overall survival compared to previous therapies, with an acceptable safety profile, indicating its potential as an effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. Mishima, S., Shitara, K.[2022]

The phase III DESTINY-Breast04 trial demonstrated that trastuzumab deruxtecan (T-DXd) is effective for patients with inoperable or metastatic HER2-low breast cancer, providing a new treatment option for this group.

Given the limited treatment options available for patients with HER2-low breast cancer, T-DXd is recommended as a new standard of care, highlighting its significance in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-DXd: New Standard for HER2-Low Breast Cancer. [2022]

References

1. France pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

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

The European Medicines Agency Review of Pertuzumab for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer: summary of the scientific assessment of the committee for medicinal products for human use. [2023]

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

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

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

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. [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. 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]

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

Trastuzumab Deruxtecan in Previously Treated Patients With HER2-Positive Metastatic Breast Cancer: Updated Survival Results From a Phase 2 Trial (DESTINY-Breast01). [2023]

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

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. [2022]

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

Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. [2022]

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

T-DXd: New Standard for HER2-Low Breast Cancer. [2022]