T-DXd Combinations for Breast Cancer

(DB-08 Trial)

Not currently recruiting at 50 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatment combinations for safety and effectiveness in people with advanced or metastatic HER2-low breast cancer. It examines how well the main drug, Trastuzumab deruxtecan (T-DXd), works with other therapies like durvalumab, capivasertib, and fulvestrant. This trial targets individuals with breast cancer that either has hormone receptors (proteins that bind hormones) or does not, and who have previously tried certain treatments. Participants should have breast cancer that has spread beyond the breast and express low levels of HER2, a protein that can promote cancer growth. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

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.

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

Research has shown that trastuzumab deruxtecan (T-DXd), tested with other medications for breast cancer treatment, generally has a manageable safety profile. In earlier studies, T-DXd demonstrated tumor-fighting abilities and was well-tolerated by patients with advanced breast cancer. However, about 65% of patients experienced a drop in neutrophil count, crucial white blood cells for fighting infections. Some patients also reported serious lung problems, requiring careful monitoring.

When combined with durvalumab and paclitaxel, previous studies indicated a favorable safety profile and positive treatment responses, suggesting good tolerance, though individual reactions may vary.

In combination with capivasertib, T-DXd continued to show a manageable safety profile, but monitoring for lung issues remains important.

For the combination of T-DXd with fulvestrant, safety data suggest it is generally tolerable, with side effects similar to those seen in other combinations.

In the group receiving T-DXd with capecitabine, past research suggests the treatment is generally tolerable but requires monitoring for potential lung issues.

Lastly, when combined with anastrozole, T-DXd maintained a consistent safety profile with previous observations, indicating it is mostly well-tolerated.

Overall, while T-DXd combinations show promise and are mostly well-tolerated, monitoring for specific side effects like lung issues and decreases in certain blood cells remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the investigational treatments combining Trastuzumab deruxtecan (T-DXd) with other drugs for breast cancer because they offer unique mechanisms and methods of action compared to current standard options like hormone therapies or chemotherapy alone. T-DXd is an antibody-drug conjugate that specifically targets cancer cells with HER2 protein overexpression, delivering a cytotoxic agent directly to the cancer cells, which could potentially enhance effectiveness and reduce side effects. When combined with other drugs like durvalumab, capivasertib, or fulvestrant, these combinations could offer a more tailored approach to attacking cancer cells, potentially leading to better outcomes. This targeted approach is different from traditional treatments, which often affect both healthy and cancerous cells, and it could provide a more efficient way to manage breast cancer with fewer side effects.

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

Research has shown that trastuzumab deruxtecan (T-DXd) holds promise for treating HER2-low breast cancer, reducing the risk of recurrence by 53%. In this trial, participants may receive T-DXd alongside other treatments. For instance, T-DXd combined with durvalumab and paclitaxel has resulted in high tumor response rates, with over two-thirds of patients in some studies showing no signs of cancer. Another trial arm will test T-DXd with capivasertib, which kept 92% of patients free from invasive disease for three years. T-DXd with fulvestrant has demonstrated strong anti-cancer effects, and when paired with capecitabine, it reduced the risk of death by 31%. Lastly, when used with anastrozole, T-DXd achieved a 97% disease control rate in patients with certain breast cancers. These findings suggest T-DXd has strong potential for treating various types of metastatic breast cancer. ^{2 3 6 7 8}

Who Is on the Research Team?

Komal Jhaveri

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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) 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) 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 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) 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04553770

Study Details | NCT04553770 | Trastuzumab Deruxtecan ... This study is evaluating how effective trastuzumab deruxtecan is at treating hormone receptor positive cancer cells that have low levels of HER2 expressed ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10324614/

Efficacy and safety of trastuzumab deruxtecan in the treatment ... In the DESTINY-Breast03 trial, the DS-8201 group achieved a disease control rate (DCR) of 97% in patients with HER2-positive advanced breast cancer, and an ...

3. onclive.com onclive.com/view/trastuzumab-deruxtecan-plus-endocrine-therapy-demonstrates-antitumor-activity-in-her2-low-hr-metastatic-breast-cancer

Trastuzumab Deruxtecan Plus Endocrine Therapy ... The median actual treatment duration in the anastrozole arm was 10.4 months (range, 2.8-22.2) for trastuzumab deruxtecan and 11.0 months (range, ...

4. enhertuhcp.com enhertuhcp.com/en/breast/efficacy/efficacy-data

Efficacy data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

5. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824000982

Trastuzumab deruxtecan in breast cancer In the most recent analysis of this trial (median follow-up 26.5 months), T-DXd was associated with an ORR of 62.0% (95% CI 54.5–69.0), a median DOR of 18.2 ...

6. enhertuhcp.com enhertuhcp.com/en/nsclc/safety

Safety Data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11178646/

Safety profile of trastuzumab deruxtecan in advanced breast ... The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical ...

8. fredhutch.org fredhutch.org/en/research/clinical-trials/trial-details.fh_trial_id_15128.trastuzumab-deruxtecan-alone-or-in-combination-with-anastrozole-for-the-treatment-of-early-stage-her2-low-hormone-receptor-positive-breast-cancer.html

Clinical Trial Details This phase II trial investigates how well trastuzumab deruxtecan works alone or in combination with anastrozole in treating patients with HER2 low, hormone ...