A Study of Dato-DXd With or Without Durvalumab Versus Investigator's Choice of Therapy in Patients With Stage I-III Triple-negative Breast Cancer Without Pathological Complete Response Following Neoadjuvant Therapy (TROPION-Breast03)

• ClinicalTrials.gov Identifier: NCT05629585
• Recruitment Status: Recruiting
• First Posted: November 29, 2022
• Last Update Posted: May 24, 2023
• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo, Inc.; SWOG Clinical Trials Partnerships
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: November 4, 2022
• First Posted Date: November 29, 2022
• Last Update Posted Date: May 24, 2023
• Actual Study Start Date: November 28, 2022
• Estimated Primary Completion Date: September 20, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 17, 2022)

Invasive disease-free survival (iDFS) for Dato-DXd + durvalumab vs. ICT [ Time Frame: From randomization until recurrence as assessed by investigator or death due to any cause up to 57 months from first subject in ]

iDFS is defined as time from randomisation until date of first occurrence of one of the following events: ipsilateral invasive breast tumour (local) recurrence, regional invasive breast cancer recurrence (axilla, regional lymph nodes, chest wall, and skin of ipsilateral breast), or distant recurrence (metastatic breast cancer that has either been biopsy-confirmed or clinically diagnosed as recurrent invasive breast cancer); contralateral invasive breast cancer; second primary non-breast invasive cancer (other than squamous or basal cell skin cancer); or death from any cause. iDFS will be determined based on disease recurrence per investigator assessment based on all available clinical assessments. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest will be the HR (hazard ratio) of iDFS for Dato-DXd + durvalumab vs ICT.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 17, 2022)

• Distant disease-free survival (DDFS) for Dato-DXd + durvalumab vs ICT [ Time Frame: Randomization to date of the event, up to 57 months from first subject in ]
  DDFS is defined as time from randomization to date of first distant recurrence, occurrence of second primary non-breast invasive cancer, or death from any cause. DDFS is determined based on disease recurrence per investigators assessment based on all available clinical assessments. The analysis will include all randomized participants, as randomized regardless of whether the participant withdraws from randomized therapy or received another anticancer therapy. The measure of interest will be the HR (hazard ratio) of DDFS for Dato-DXd + durvalumab vs ICT.
• DDFS for Dato-DXd vs ICT [ Time Frame: Randomization to date of the event, up to 57 months from first subject in ]
  DDFS is defined as time from randomization to date of first distant recurrence, occurrence of second primary non-breast invasive cancer, or death from any cause. DDFS is determined based on disease recurrence per investigators assessment based on all available clinical assessments. The measure of interest will be the HR of DDFS for Dato-DXd vs ICT.
• DDFS for Dato-DXd + durvalumab vs Dato-DXd [ Time Frame: Randomization to date of the event, up 57 months from first subject in ]
  DDFS is defined as time from randomization to date of first distant recurrence, occurrence of second primary non-breast invasive cancer, or death from any cause. DDFS is determined based on disease recurrence per investigators assessment based on all available clinical assessments. The measure of interest will be the HR of DDFS for Dato-DXd + durvalumab vs Dato-DXd.
• Overall Survival (OS) for Dato-DXd + durvalumab vs ICT [ Time Frame: Randomization to date of death, due to any cause, up to 87 months from first subject in ]
  OS is defined as time from randomization until date of death due to any cause. The analysis will include all randomised participants, as randomised regardless of whether the participant withdraws from randomised therapy or received another anticancer therapy. The measure of interest will be the HR (hazard ratio) of OS for Dato-DXd + durvalumab vs ICT.
• OS for Dato-DXd vs ICT [ Time Frame: Randomization to date of death, due to any cause, up to 87 months from first subject in ]
  OS is defined as time from randomization until date of death due to any cause. The measure of interest will be the HR of OS for Dato-DXd vs ICT.
• iDFS for Dato-DXd vs ICT [ Time Frame: Randomization to event, up to 57 months from first subject in ]
  iDFS is defined as time from randomisation until date of first occurrence of one of the following events: ipsilateral invasive breast tumour (local) recurrence, regional invasive breast cancer recurrence (axilla, regional lymph nodes, chest wall, and skin of ipsilateral breast), or distant recurrence (metastatic breast cancer that has either been biopsy-confirmed or clinically diagnosed as recurrent invasive breast cancer); contralateral invasive breast cancer; second primary non-breast invasive cancer (other than squamous or basal cell skin cancer); or death from any cause. iDFS will be determined based on disease recurrence per investigator assessment based on all available clinical assessments. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest will be the HR of iDFS for Dato-DXd vs ICT.
• iDFS for Dato-DXd + durvalumab vs Dato-DXd [ Time Frame: Randomization to event, up to 57 months from first subject in ]
  iDFS is defined as time from randomisation until date of first occurrence of one of the following events: ipsilateral invasive breast tumour (local) recurrence, regional invasive breast cancer recurrence (axilla, regional lymph nodes, chest wall, and skin of ipsilateral breast), or distant recurrence (metastatic breast cancer that has either been biopsy-confirmed or clinically diagnosed as recurrent invasive breast cancer); contralateral invasive breast cancer; second primary non-breast invasive cancer (other than squamous or basal cell skin cancer); or death from any cause. The measure of interest will be the HR of iDFS for Dato-DXd + durvalumab vs Dato-DXd.
• Time to Deterioration (TTD) in physical functioning in participants treated with Dato-DXd with or without durvalumab compared with ICT [ Time Frame: Randomization to date of the event, up to 36 months after randomization ]
  TTD in physical function as measured by the PROMIS Physical Function Short Form 8c.TTD is defined as time from the date of randomisation to the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold. The analysis will include all dosed participants. The measure of interest is the HR (hazard ratio) of TTD in physical function for Dato-DXd with or without durvalumab compared with ICT.
• Time to Deterioration (TTD) in GHS/QoL in participants treated with Dato-DXd with or without durvalumab compared with ICT [ Time Frame: Randomization to date of the event, up to 36 months after randomization ]
  TTD in GHS/QoL as measured by the GHS/QoL scale from the EORTC IL172. TTD is defined as time from the date of randomisation to the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold. The analysis will include all randomised participants. The measure of interest is the HR (hazard ratio) of TTD in GHS/QoL for Dato-DXd with or without durvalumab compared with ICT.
• Fatigue in participants treated with Dato-DXd with or without durvalumab vs ICT [ Time Frame: Randomization to 24 months after randomization ]
  Proportion of participants experiencing different levels of fatigue at 3 months (13weeks), 6 months (26 weeks), and 12 months (52 weeks) as measured by PROMIS Fatigue Short Form 7a. The analysis will include all dosed participants. The measure of interest will be the proportion of participants reporting different levels of fatigue.
• Pharmacokinetics of Dato-DXd [ Time Frame: Day 1 of cycles 1,2,4,6,8 (Each cycle is 21 days) ]
  Concentration of Dato- DXd, total anti-TROP2 antibody, and MAAA-1181 in plasma.
• Immunogenicity of Dato-DXd [ Time Frame: Day 1 of cycles 1,2,4,6,8 (Each cycle is 21 days) and within 35 days of completion of or discontinuation of study intervention (at an average of 6 months following randomization) ]
  Presence of ADAs for Dato-DXd (confirmatory results: positive or negative; titres).
• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: Randomization to final safety follow-up visit, either 90 days after last dose of study intervention for those who complete planned study intervention or 90 days after date of discontinuation for those who discontinue study intervention prematurely ]
  Safety and tolerability will be evaluated in terms of AEs (graded by CTCAE version 5.0).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Dato-DXd With or Without Durvalumab Versus Investigator's Choice of Therapy in Patients With Stage I-III Triple-negative Breast Cancer Without Pathological Complete Response Following Neoadjuvant Therapy (TROPION-Breast03)
• Official Title: A Phase 3 Open-label, Randomised Study of Datopotamab Deruxtecan (DatoDXd) With or Without Durvalumab Versus Investigator's Choice of Therapy in Patients With Stage I-III Triple-negative Breast Cancer Who Have Residual Invasive Disease in the Breast and/or Axillary Lymph Nodes at Surgical Resection Following Neoadjuvant Systemic Therapy (TROPION-Breast03)
• Brief Summary: This is a Phase III, randomized, open-label, 3-arm, multicenter, international study assessing the efficacy and safety of Dato-DXd with or without durvalumab compared with ICT in participants with stage I to III TNBC with residual invasive disease in the breast and/or axillary lymph nodes at surgical resection following neoadjuvant systemic therapy.

Detailed Description

The study will investigate the efficacy and safety of Dato-DXd with or without durvalumab when compared with ICT (capecitabine and/or pembrolizumab) in participants with stage I to III TNBC who have residual invasive disease in the breast and/or axillary lymph nodes at surgical resection following neoadjuvant systemic therapy.

The primary objective of the study is to demonstrate superiority of Dato-DXd in combination with durvalumab relative to ICT by assessment of iDFS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Parallel

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Breast Cancer

Intervention

• Drug: Dato-DXd
  Experimental drug. Provided in 100mg vials. IV infusion
  Other Name: Datopotamab deruxtecan (Dato-DXd, DS-1062a)
• Drug: Durvalumab
  Experimental drug. Provided in 50mg vials. IV infusion
  Other Name: MEDI4736
• Drug: Capecitabine
  Active Comparator. Tablet. Oral route of administration
  Other Name: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord
• Drug: Pembrolizumab
  Active Comparator. Provided in 100mg vials. IV infusion
  Other Name: KEYTRUDA®

Study Arms

• Experimental: Dato-DXd in combination with Durvalumab
  Arm 1: Dato-DXd 6 mg/kg IV Q3W x 8 cycles + Durvalumab 1120 mg IV Q3W x 9 cycles
  Interventions:

  • Drug: Dato-DXd
  • Drug: Durvalumab
• Experimental: Dato-DXd
  Arm 2: Dato-DXd 6 mg/kg IV Q3W x 8 cycles
  Intervention: Drug: Dato-DXd
• Active Comparator: Investigators Choice Therapy

  Arm 3: Capecitabine (1000 or 1250 mg/m2 oral BID on Days 1 to 14, Q3W) for 8 cycles

  Pembrolizumab* (200 mg IV on Day 1, Q3W) for 9 cycles

  Capecitabine (1000 or 1250 mg/m2 oral BID on Days 1 to 14, Q3W) for 8 cycles + pembrolizumab* (200 mg IV on Day 1, Q3W) for 9 cycles

  * Only participants who have received prior pembrolizumab in the neoadjuvant setting should receive pembrolizumab as part of their adjuvant therapy on Arm 3.

  Interventions:

  • Drug: Capecitabine
  • Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 17, 2022): 1075
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 26, 2030
• Estimated Primary Completion Date: September 20, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Participant must be ≥ 18 years at the time of screening.
2. Histologically confirmed invasive TNBC, as defined by the ASCO/CAP guidelines.
3. Residual invasive disease in the breast and/or axillary lymph node(s) at surgical resection following neoadjuvant therapy.
4. Completed at least 6 cycles of neoadjuvant therapy containing an anthracycline and/or a taxane with or without carboplatin, with or without pembrolizumab.
5. No evidence of locoregional or distant relapse.
6. Surgical removal of all clinically evident disease in the breast and lymph nodes.
7. ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to randomisation.
8. All participants must provide an FFPE tumour sample from residual invasive disease at surgery for tissue-based analysis.
9. No adjuvant systemic therapy.
10. Radiotherapy (if indicated) delivered before the start of study intervention.
11. If post-operative radiation therapy is given, an interval of no more than 6 weeks between the completion of radiation therapy and the date of randomisation (radiation therapy can be completed during screening period). If no post-operative radiation therapy is given, an interval of no more than 16 weeks between the date of breast surgery and the date of randomisation.
12. Has LVEF ≥ 50% by either an ECHO or MUGA scan within 28 days before randomisation.
13. Eligible for one of the therapy options listed as investigator's choice per investigator assessment.
14. No known germline BRCA1 or BRCA2 mutation.
15. Adequate bone marrow reserve and organ function within 7 days before randomisation.

Exclusion Criteria:

1. Stage IV (metastatic) TNBC.
2. History of prior invasive breast cancer, or evidence of recurrent disease following preoperative therapy and surgery.
3. Severe or uncontrolled medical conditions including systemic diseases, history of allogeneic organ transplant and active bleeding diseases, ongoing or active infection, serious chronic gastrointestinal conditions associated with diarrhea .
4. History of another primary malignancy except for adequately resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, in situ disease that has undergone potentially curative therapy, or other solid malignancy treated with curative intent with no known active disease within 5 years before randomisation and of low potential risk for recurrence.
5. Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to Grade ≤ 1 or baseline. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss).
6. Active or prior documented autoimmune or inflammatory disorders.
7. Clinically significant corneal disease.
8. Active or uncontrolled hepatitis B or C virus infection.
9. Known to have tested positive for HIV (positive HIV 1/2 antibodies).
10. Active tuberculosis infection.
11. Mean resting corrected QTcF > 470 ms regardless of gender, obtained from triplicate 12-lead ECGs performed at screening.
12. Uncontrolled or significant cardiac disease.
13. History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
14. Clinically severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.
15. Any known active liver disease.
16. Grade ≥ 2 peripheral neuropathy of any aetiology.
17. Prior exposure to a PD-1/PD-L1 inhibitor other than pembrolizumab.
18. Current or prior use of immunosuppressive medication within 14 days prior to randomisation.
19. Participants with a known severe hypersensitivity to Dato-DXd or any of the excipients of these products including but not limited to polysorbate 80 or other monoclonal antibodies.
20. Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors.
21. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to randomisation, randomisation into a prior Dato-DXd, T-DXd, or durvalumab study regardless of treatment assignment.
22. Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Belgium, Brazil, Canada, China, Denmark, France, Germany, Greece, Italy, Japan, Korea, Republic of, Spain, Sweden, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT05629585
• Other Study ID Numbers: D926XC00001; 2022-002680-30 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current

Collaborators

• Daiichi Sankyo, Inc.
• SWOG Clinical Trials Partnerships

Investigators

• Study Chair: Aditya Bardia, MD, MPH; Massachusetts General Hospital

• PRS Account: AstraZeneca
• Verification Date: May 2023