Dato-DXd + T-DXd for Breast Cancer

(TRADE DXd Trial)

Overseen by Ana C. Garrido-Castro

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Ana C Garrido-Castro, MD

Must not be taking: Topoisomerase inhibitors

Disqualifiers: Corneal disease, Pneumonitis, Uncontrolled infection, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety and effectiveness of the sequence of two investigational drugs (trastuzumab deruxtecan followed by datopotamab deruxtecan, or datopotamab deruxtecan followed by trastuzumab deruxtecan) to learn whether the treatment works in treating HER2-low metastatic breast cancer. The names of the study drugs involved in this study are: * Datopotamab deruxtecan (a type of antibody drug conjugate) * Trastuzumab deruxtecan (a type of antibody drug conjugate)

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

The trial protocol does not specify if you need to stop all current medications. However, you must stop any prior chemotherapy, biologic, or targeted therapy at least 14 days before starting the study treatment. You can continue taking bisphosphonates or RANK ligand inhibitors if needed.

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

Research shows that Datopotamab Deruxtecan (Dato-DXd) is being studied for its effectiveness in treating certain types of breast cancer, and it has shown promise in patients with advanced or metastatic non-small cell lung cancer. Trastuzumab Deruxtecan (T-DXd) has demonstrated effectiveness in improving survival in patients with HER2-positive metastatic breast cancer and is being explored for other cancers as well. ^{1 2 3 4 5}

Is the combination of Dato-DXd and T-DXd generally safe for humans?

Trastuzumab deruxtecan (T-DXd) has shown a generally manageable safety profile, with common side effects including low-grade blood and digestive issues. However, serious lung problems have been observed in some patients. Datopotamab deruxtecan (Dato-DXd) is currently being studied for safety in a phase 3 trial for breast cancer. ^{3 6 7 8 9}

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

Dato-DXd and T-DXd are unique because they are antibody-drug conjugates, which means they combine a targeted antibody with a cancer-killing drug. This approach allows them to specifically target cancer cells, potentially offering a more effective treatment option for patients with certain types of breast cancer who have limited options beyond traditional chemotherapy. ^{3 4 10 11 12}

Research Team

Ana C. Garrido-Castro

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for individuals with HER2-low metastatic breast cancer. Participants should be those whose cancer has not responded to previous treatments (ADC-refractory). Specific eligibility criteria are not provided, but typically include factors like age, health status, and prior therapies.

Inclusion Criteria

I stopped any experimental cancer treatments 21 days before starting this study.

I am 18 years old or older.

I am eligible even with new or worsening brain metastases under certain conditions.

Exclusion Criteria

Concurrent use of any other investigational or study agents that are being used to treat the underlying malignancy.

Corrected QT interval prolongation.

My HIV infection is not well controlled.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Datopotamab deruxtecan or Trastuzumab deruxtecan in 21-day cycles, with imaging every 9 weeks

Up to 36 months

Cycle 1 through end of treatment: Day 1 of 21-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment with imaging every 9 weeks

Up to 36 months

Imaging every 9 weeks

Long-term Follow-up

Participants are followed approximately every six months after the study treatment ends

Up to 5 years

Visits every 6 months

Treatment Details

Interventions

• Datopotamab Deruxtecan (Antibody Drug Conjugate)
• Trastuzumab Deruxtecan (Antibody Drug Conjugate)

Trial Overview The study tests the safety and effectiveness of two drugs: Datopotamab Deruxtecan and Trastuzumab Deruxtecan. It explores whether using these drugs in sequence can treat this type of breast cancer effectively.

Participant Groups

Group I: Arn B (ADC1 T-DXd HR-) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and echocardiogram. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through end of treatment: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group II: Arm H (ADC2 T-DXd HR-) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, echocardiogram. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 1 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group III: Arm G (ADC2 T-DXd HR+) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, echocardiogram. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 1 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group IV: Arm F (ADC2 Dato-DXd HR-) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, eye exam. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 1 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group V: Arm E (ADC2 Dato-DXd HR+) Experimental Treatment 1 Intervention

Participants will complete: * Baseline visit with imaging, tumor biopsy, electrocardiogram, eye exam. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group VI: Arm D (ADC1 Dato-DXd HR-) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and eye exam. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group VII: Arm C (ADC1 Dato-DXd HR+) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and eye exam. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through end of treatment: --Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Datopotamab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, eye exam. * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Group VIII: Arm A (ADC1 T-DXd HR+) Experimental Treatment 1 Intervention

Enrolled participants will complete: * Baseline visit with tumor biopsy, imaging, electrocardiogram and echocardiogram. * Tumor biopsy between Cycle 2 Day 1 and Day 8. * Imaging every 9 weeks. * Cycle 1 through Cycle 3: --Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Cycle 4 through end of treatment: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab deruxtecan 1x daily. * Imaging on Day 1. * End of Treatment visit with imaging, tumor biopsy, echocardiogram * Follow up: imaging every 9 weeks. * Long-term Follow Up: visits every 6 months.

Who Is Running the Clinical Trial?

Ana C Garrido-Castro, MD

Lead Sponsor

Trials

2

Recruited

470+

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

Translational Breast Cancer Research Consortium

Collaborator

Trials

27

Recruited

3,100+

Findings from Research

In a phase I trial, the TROP2-directed antibody-drug conjugate datopotamab deruxtecan showed promising activity in patients with advanced or metastatic non-small cell lung cancer, with nearly 25% of participants responding to the treatment.

The treatment was associated with manageable side effects, suggesting it could be a safe option for patients with this type of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROP2 ADC Intrigues in NSCLC. [2021]

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]

Datopotamab deruxtecan (Dato-DXd) is a promising new treatment for patients with metastatic HR+/HER2- breast cancer, particularly for those who have limited options after endocrine therapy and chemotherapy.

The ongoing phase III TROPION-Breast01 study is comparing the efficacy and safety of Dato-DXd against standard chemotherapy in patients who have already received one or two lines of systemic treatment, aiming to improve outcomes in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Bardia, A., Jhaveri, K., Kalinsky, K., 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 (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

In a real-world study of 143 patients with HER2+ metastatic breast cancer, trastuzumab deruxtecan (T-DXd) demonstrated a high overall response rate of 68% and a median progression-free survival of 16 months, confirming its efficacy in routine clinical practice.

The safety profile of T-DXd was consistent with previous studies, with 59% of patients experiencing any-grade toxicity, primarily nausea and neutropenia, but no new safety concerns were identified, indicating it is a well-tolerated treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Outcomes of Trastuzumab Deruxtecan in Patients With HER2+ Metastatic Breast Cancer: The DE-REAL Study. Botticelli, A., Caputo, R., Scagnoli, S., et al.[2023]

In a phase II study involving 152 patients with HER2-mutant metastatic non-small-cell lung cancer, trastuzumab deruxtecan (T-DXd) showed a confirmed objective response rate of 49% at 5.4 mg/kg and 56% at 6.4 mg/kg, indicating robust antitumor activity.

The safety profile of T-DXd was generally manageable, with fewer severe adverse events reported in the 5.4 mg/kg group compared to the 6.4 mg/kg group, suggesting that the lower dose may be preferable for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. Goto, K., Goto, Y., Kubo, T., et al.[2023]

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]

In an expanded-access study involving 64 patients with HER2-positive gastric or gastroesophageal junction adenocarcinomas, trastuzumab deruxtecan (T-DXd) was administered safely, with no new safety concerns identified prior to its marketing approval in Japan.

Serious adverse events (SAEs) were reported in 26.6% of patients, with febrile neutropenia being the most common; however, drug-related SAEs led to death in only one patient, indicating a manageable safety profile for T-DXd.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. Shitara, K., Yamaguchi, K., Muro, K., 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]

In a study of 22 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan (T-DXd) showed a median progression-free survival of 9.7 months and an objective response rate of 61.9%, indicating its efficacy as a treatment option.

T-DXd was particularly effective in patients with heterogeneous or reduced HER2 expression, achieving partial responses in patients who did not respond to the previous treatment with ado-trastuzumab emtansine (T-DM1), highlighting its potential to overcome resistance in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. Nakajima, H., Harano, K., Nakai, T., et al.[2022]

References

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

TROP2 ADC Intrigues in NSCLC. [2021]

2. 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]

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

TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. [2023]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

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

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

Trastuzumab Deruxtecan: First Approval. [2020]

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

Real-World Outcomes of Trastuzumab Deruxtecan in Patients With HER2+ Metastatic Breast Cancer: The DE-REAL Study. [2023]

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

Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. [2023]

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

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

10. Japan pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. [2023]

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

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

12. Netherlands pubmed.ncbi.nlm.nih.gov

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. [2022]