TReatment of ADC-Refractory Breast CancEr With Dato-DXd or T-DXd: TRADE DXd

NCT06533826 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 24-251TBCRC-064
• Study Type: interventional
• Target: 357
• Locations: 1 country
• Sites: 11

Brief Summary

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-negative (HER2-low or HER2-0) 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)

Conditions

Breast Cancer; HER2-low Breast Cancer; Metastatic Breast Cancer; HER2-negative Breast Cancer

Keywords

Breast Cancer; HER2-low Breast Cancer; Metastatic Breast Cancer; HER2-negative Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate in ADC1 (Group 1) Cohort

  Objective response rate (ORR), defined as best overall response of either complete or partial response, will be assessed among participants who start protocol therapy and have measurable disease at screening. Radiographic response will be assessed using RECIST 1.1 criteria as defined per protocol.

  The observation period related to this endpoint is up to 36 months.

• Objective Response Rate in ADC2 (Group 2) Cohort

  Objective response rate (ORR), defined as best overall response of either complete or partial response, will be assessed among participants who start protocol therapy and have measurable disease at screening. Radiographic response will be assessed using RECIST 1.1 criteria as defined per protocol.

  The observation period related to this endpoint is up to 36 months.

Secondary Outcomes (17)

• Median Progression Free Survival in ADC1 (Group 1) Cohort

  The observation period related to this endpoint is up to 36 months.

• Median Overall Survival (OS) in ADC1 (Group 1) Cohort

  The observation period related to this endpoint is up to 5 years.

• Clinical Benefit Rate (CBR) in ADC1 (Group 1) Cohort

  The observation period related to this endpoint is up to 36 months.

• Time to Progression (TTP) in ADC1 (Group 1) Cohort

  The observation period related to this endpoint is up to 36 months.

• Time to Response (TTR) in ADC1 (Group 1) Cohort

  The observation period related to this endpoint is up to 36 months.

Study Arms (8)

Arm A (ADC1 T-DXd HR+)

EXPERIMENTAL

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.

Drug: Trastuzumab Deruxtecan

Arn B (ADC1 T-DXd HR-)

EXPERIMENTAL

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.

Drug: Trastuzumab Deruxtecan

Arm C (ADC1 Dato-DXd HR+)

EXPERIMENTAL

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.

Drug: Datopotamab Deruxtecan

Arm D (ADC1 Dato-DXd HR-)

EXPERIMENTAL

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.

Drug: Datopotamab Deruxtecan

Arm E (ADC2 Dato-DXd HR+)

EXPERIMENTAL

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.

Drug: Datopotamab Deruxtecan

Arm F (ADC2 Dato-DXd HR-)

EXPERIMENTAL

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.

Drug: Datopotamab Deruxtecan

Arm G (ADC2 T-DXd HR+)

EXPERIMENTAL

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.

Drug: Trastuzumab Deruxtecan

Arm H (ADC2 T-DXd HR-)

EXPERIMENTAL

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.

Drug: Trastuzumab Deruxtecan

Interventions

Trastuzumab Deruxtecan DRUG

A HER2-directed ADC, 100mg/vial, via intravenous (into the vein) infusion per protocol.

Also known as: Enhertu, am-trastuzumab deruxtecan-nxki, T-DXd, DS-8201a

Arm A (ADC1 T-DXd HR+); Arm G (ADC2 T-DXd HR+); Arm H (ADC2 T-DXd HR-); Arn B (ADC1 T-DXd HR-)

Datopotamab Deruxtecan DRUG

A TROP2-directed antibody drug conjugate, 100mg/vial, via intravenous (into the vein) infusion per protocol.

Also known as: Dato-DXd, DS-1062, DS-1062a

Arm C (ADC1 Dato-DXd HR+); Arm D (ADC1 Dato-DXd HR-); Arm E (ADC2 Dato-DXd HR+); Arm F (ADC2 Dato-DXd HR-)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed invasive breast cancer with unresectable locally advanced or metastatic disease. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation; i.e., visible chest wall disease or metastases on imaging meeting standard radiology criteria (i.e., lymph nodes larger than 1 cm in the short axis diameter).
• The most recent pathology results will be considered for enrollment according to local testing of ER, PR and HER2 in a CLIA-certified environment. ER, PR and HER2 status per local testing must be known prior to study registration.
• Participants must have history of HER2-low or HER2-0 breast cancer per local testing, and no known history of HER2-positive breast cancer. All available prior HER2 pathology results must be HER2-low or HER2-0; no known HER2 IHC 3+ or ISH-amplified breast cancer is allowed.
• HER2-low status is defined as IHC 1+ or 2+/ISH non-amplified breast cancer in any prior tumor sample (e.g., primary or metastatic tumor) collected prior to study enrollment: IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested (note: ISH may be determined by either fluorescence in situ hybridization \[FISH\] or dual in situ hybridization \[DISH\])
• HER2-0 status is defined as IHC 0 (null or ultra-low) in all prior tumor samples with available HER2 pathology results: IHC 0+/ISH- or IHC 0+/ISH untested (IHC 0+: IHC 0 absent membrane staining \[null\] or IHC 0 with membrane staining \>0 and \<1+ \[ultralow\]). Note: Enrollment of patients with HER2-0 breast cancer will be capped at 15% in each ADC1 and ADC2 cohort.
• Participants with any HR status will be allowed on study.
• HR-positive cohorts: ER and/or PR expression ≥1%
• HR-negative cohorts: ER and PR expression \<1%
• All cohorts: The most recent HER2 pathology result must be HER2-0 or HER2-low (i.e., must not be HER2-positive).
• HER2-0: IHC 0+/ISH- or IHC 0+/ISH untested.
• HER2-low: IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested (note: ISH may be determined by either fluorescence in situ hybridization \[FISH\] or dual in situ hybridization \[DISH\]).
• Participants must have measurable disease per RECIST 1.1.
• Participants must be willing to undergo research tissue biopsies (at baseline prior to ADC1, after 3 weeks of treatment with ADC1, at progression on ADC1 or baseline prior to ADC2, and at progression on ADC2), if tumor is safely accessible.
• Prior endocrine therapy: Participants with HR-positive breast cancer considered to be candidates for endocrine therapy must have: a) progressed on or within 12 months of adjuvant endocrine therapy or received at least one line of endocrine therapy in the metastatic setting, and b) received prior CDK4/6 inhibitor. Prior endocrine therapy does not require washout.
• Prior chemotherapy: Prior lines of chemotherapy allowed in the metastatic setting are specified below. Prior topoisomerase I inhibitor therapy is not allowed in any setting, except as specified below for ADC2 cohorts. Participants may have discontinued all chemotherapy at least 14 days prior to study treatment initiation. All toxicities related to prior chemotherapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol, except alopecia (any grade allowed) and neuropathy (grade 2 or lower allowed).

You may not qualify if:

• Concurrent use of any other investigational or study agents that are being used to treat the underlying malignancy.
• Any prior treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I, except as specified per protocol for ADC2 cohorts.
• Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention.
• Clinically significant corneal disease.
• History of severe hypersensitivity reactions to either trastuzumab deruxtecan or datopotamab deruxtecan or their inactive ingredients.
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Major surgery within 2 weeks prior to study treatment initiation.
• Uncontrolled, significant intercurrent or recent illness including, but not limited to, ongoing or active infection, uncontrolled non-malignant systemic disease, uncontrolled seizures, or psychiatric illness/social situation that would limit compliance with study requirements in the opinion of the treating investigator.
• History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. For ADC2 cohorts, if a participant experienced G1 pneumonitis/ILD with ADC1 (e.g., treated with steroids) with complete resolution of radiographic findings and ability to resume ADC1 within 12 weeks of the scheduled interruption without recurrence of ILD, the participant may enroll to ADC2.
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), and prior complete pneumonectomy.
• Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \>450 msec (males).
• Any of the following procedures or conditions in 6 months prior to enrollment: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure (New York Heart Association Functional Classification Grade ≥2), and stroke.
• Individuals with a history of a second malignancy are ineligible except for the following circumstances:
• Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy.
• Individuals with the following cancers that have been diagnosed and treated within the past 3 years are eligible: cervical/prostate carcinoma in situ, superficial bladder cancer, non-melanoma cancer of the skin.

Sponsors & Collaborators

• Ana C Garrido-Castro, MD: lead
• AstraZeneca: collaborator
• Translational Breast Cancer Research Consortium: collaborator

Study Sites (11)

University of Alabama

Birmingham, Alabama, 35294, United States

RECRUITING

University of San Francisco

San Francisco, California, 94158, United States

RECRUITING

Yale University Cancer Center

New Haven, Connecticut, 06520, United States

RECRUITING

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

RECRUITING

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

Montefiore Einstein Comprehensive Cancer Center

The Bronx, New York, 10461, United States

RECRUITING

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

RECRUITING

Vanderbilt Cancer Center

Nashville, Tennessee, 37232, United States

RECRUITING

Baylor College of Medicine

Houston, Texas, 77030, United States

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Ana Garrido-Castro, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ana Garrido-Castro, MD

CONTACT

617-632-3800; ana_garrido-castro@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: July 26, 2024
• First Posted: August 1, 2024
• Study Start: October 29, 2024
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): August 1, 2038
• Last Updated: October 24, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (11)