T-DXd Combinations for Breast Cancer

(DB-08 Trial)

Recruiting at 42 trial locations

Overseen By AZ Breast Cancer Study Navigators

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must not be taking: IV antibiotics, antivirals

Disqualifiers: Cardiovascular disease, ILD, CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

138 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It might depend on the specific medications you are taking, so it's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug T-DXd for breast cancer?

Research shows that T-DXd is effective in treating HER2-positive metastatic breast cancer, with studies indicating it outperforms other treatments like capecitabine-based chemotherapy and T-DM1. It has shown a high overall response rate and durable responses, making it a promising option for patients with limited treatment choices. ^{1 2 3 4 5}

Is trastuzumab deruxtecan (T-DXd) safe for humans?

Trastuzumab deruxtecan (T-DXd) has been shown to be generally safe in humans, but it can cause serious side effects like interstitial lung disease (lung inflammation), neutropenia (low white blood cell count), and heart problems. Common side effects include nausea, fatigue, and hair loss. It is important to discuss these risks with your doctor. ^{2 3 4 6 7}

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

T-DXd is unique because it is an antibody-drug conjugate specifically targeting HER2, showing effectiveness in both HER2-positive and HER2-low breast cancer, where treatment options are limited. It has demonstrated superior performance compared to other therapies like capecitabine-based chemotherapy and T-DM1, and is considered a new standard of care for HER2-low breast cancer. ^{2 5 7 8 9}

What is the purpose of this trial?

This trial is testing T-DXd with other treatments in patients with a specific type of advanced breast cancer that has low levels of HER2. The study aims to find the best dose and see how well the treatment works and how safe it is. T-DXd is a new treatment that has shown promising outcomes in various studies for advanced breast cancers with different levels of HER2.

Research Team

Komal Jhaveri

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with HER2-low advanced or metastatic breast cancer. Eligible patients must have received certain prior treatments depending on their hormone receptor status, and should not have significant lung disease, uncontrolled infections or illnesses, cardiovascular issues, a history of specific lung conditions, primary immunodeficiency, spinal cord compression or active brain metastases.

Inclusion Criteria

I have HR- breast cancer and have had specific prior treatments depending on the study part.

If you have hormone receptor-positive breast cancer, for Part 1, you must have had at least one treatment with hormonal therapy, with or without a targeted therapy, and at least one treatment with chemotherapy for metastatic breast cancer. For Part 2, you can have only one prior treatment with hormonal therapy, with or without a targeted therapy, and no prior chemotherapy in the metastatic setting.

I am fully active or can carry out light work.

Exclusion Criteria

I have or had lung inflammation treated with steroids, or it can't be ruled out by scans.

I have been treated with a specific drug that targets cancer cells.

I do not have any uncontrolled illnesses.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-finding

Participants receive T-DXd in combination with other therapies to determine the recommended phase 2 dose (RP2D)

Up to 24 months

Dose-expansion

Participants receive T-DXd at the RP2D to further assess safety, tolerability, and anti-tumor activity

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 24 months

Treatment Details

Interventions

• Anastrozole
• Capecitabine
• Capivasertib
• Durvalumab
• Fulvestrant
• Paclitaxel
• Trastuzumab deruxtecan

Trial Overview The DESTINY-Breast 08 study tests the combination of T-DXd (Trastuzumab deruxtecan) with other therapies like Fulvestrant, Durvalumab, Capivasertib, Anastrozole, Paclitaxel and Capecitabine in treating HER2-low advanced/metastatic breast cancer to evaluate safety and early anti-tumor effects.

Participant Groups

Group I: Module 5: T-DXd + fulvestrant Experimental Treatment 2 Interventions

T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use

Group II: Module 4: T-DXd + anastrozole Experimental Treatment 2 Interventions

T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral

Group III: Module 3: T-DXd + capivasertib Experimental Treatment 2 Interventions

T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use

Group IV: Module 2: T-DXd + durvalumab + paclitaxel Experimental Treatment 3 Interventions

T-DXd: 5.4 mg/kg Q3W, intravenous use Durvalumab: 1120 mg Q3W, intravenous use Paclitaxel: 80 mg/m2 QW in 3-week cycles, intravenous use

Group V: Module 1: T-DXd + capecitabine Experimental Treatment 2 Interventions

T-DXd: 5.4 mg/kg Q3W, intravenous use Capecitabine: 1000mg/m2 BID, days 1-14 Q3W, oral use

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

Approved in European Union as Arimidex for:

• Breast cancer
• Early breast cancer in postmenopausal women

Approved in United States as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer

Approved in Canada as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• Treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Approved in Japan as Arimidex for:

• 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+

Daiichi Sankyo Co., Ltd.

Industry Sponsor

Trials

116

Recruited

49,200+

Findings from Research

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) has shown superior efficacy compared to capecitabine-based chemotherapy and T-DM1 in patients with metastatic HER2-positive breast cancer, based on the latest phase III data from the DESTINY-Breast02 and DESTINY-Breast03 trials.

T-DXd may also be effective as a neoadjuvant treatment for HER2-low breast cancer, suggesting its potential for broader applications in HER2-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-DXd Keeps Shining in Breast Cancer. [2023]

In the DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd) demonstrated superior progression-free survival and overall survival compared to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer, while maintaining quality of life (QoL) throughout treatment.

Patients receiving T-DXd experienced a median time to first hospitalization that was three times longer than those on T-DM1, indicating better overall health management and fewer hospital visits during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Curigliano, G., Dunton, K., Rosenlund, M., et al.[2023]

Fam-trastuzumab deruxtecan-nxki (ENHERTU) received accelerated FDA approval for treating HER2-positive breast cancer in patients who have already undergone two or more anti-HER2 therapies, based on a study involving 184 patients that showed a confirmed overall response rate of 60.3%.

While ENHERTU is effective, it carries significant risks, including severe interstitial lung disease and neutropenia, highlighting the importance of monitoring for serious side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. Narayan, P., Osgood, CL., Singh, H., et al.[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]

Trastuzumab deruxtecan (T-DXd) was evaluated for safety in 1457 patients across 8 clinical trials, revealing that gastrointestinal disorders and blood-related issues were the most common adverse events, with neutropenia being the most severe (21.4% incidence).

The study highlighted significant concerns regarding interstitial lung disease (10.9% incidence) and decreased left ventricular ejection fraction (1.2% incidence), suggesting that while T-DXd is generally well tolerated, these specific side effects require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of trastuzumab deruxtecan: A meta-analysis and pharmacovigilance study. Guo, Z., Ding, Y., Wang, M., et al.[2023]

In the phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan (T-DXd) showed a remarkable objective response rate of 60.9% and a median progression-free survival of 16.4 months in HER2+ metastatic breast cancer patients, supporting its use after multiple prior treatments.

While T-DXd is effective, it has a notable side effect of pneumonitis occurring in 13.6% of patients, leading to warnings for interstitial lung disease and embryo-fetal toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan for HER2+ advanced breast cancer. Lee, J., Park, YH.[2022]

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that effectively targets HER2-positive unresectable/metastatic breast cancer, showing a generally manageable safety profile with common low-grade side effects like nausea and neutropenia, but also carries risks of severe interstitial lung disease (ILD)/pneumonitis.

Effective management strategies for T-DXd-related adverse events, particularly proactive measures for nausea and ILD/pneumonitis, are crucial for maximizing treatment benefits and minimizing the risk of treatment discontinuation or dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. Rugo, HS., Bianchini, G., Cortes, J., et al.[2022]

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]

References

1. 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]

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

T-DXd Keeps Shining in Breast Cancer. [2023]

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

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. [2023]

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

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. [2022]

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

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

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

Safety of trastuzumab deruxtecan: A meta-analysis and pharmacovigilance study. [2023]

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

Trastuzumab deruxtecan for HER2+ advanced breast cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. [2022]

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

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