A Phase 3 Open-label, Randomised Study of Datopotamab Deruxtecan (Dato-DXd) 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)

Cancer Categories

Breast

Karmanos Trial ID

2023-027

NCT ID

NCT05629585

Age Group

Adult

Scope

National

Phase

Phase III

Principal Investigator

Jailan
Elayoubi, M.D.
Oncology - Medical View Profile

Objective:

Primary Objectives

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

Key secondary

To demonstrate superiority of Dato-DXd in combination with durvalumab relative to ICT by assessment of DDFS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To demonstrate superiority of Dato-DXd in combination with durvalumab relative to ICT by assessment of OS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To demonstrate superiority of Dato-DXd monotherapy 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.

Secondary

To assess the efficacy of Dato-DXd monotherapy relative to ICT by assessment of DDFS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To assess the efficacy of Dato-DXd monotherapy relative to ICT by assessment of OS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To assess the efficacy of Dato-DXd in combination with durvalumab relative to Dato-DXd monotherapy by assessment of iDFS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To assess the efficacy of Dato-DXd in combination with durvalumab relative to Dato-DXd monotherapy by assessment of DDFS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To assess participant-reported physical function, by assessment of TTD, in participants treated with Dato-DXd with or without durvalumab compared with ICT.
To assess participant-reported GHS/QoL, by assessment of TTD, in participants treated with Dato-DXd with or without durvalumab compared with ICT.
To assess participant-reported fatigue in participants treated with Dato-DXd with or without durvalumab compared with ICT.
To assess the PK of Dato-DXd (in both the monotherapy arm and in combination with durvalumab)
To investigate the immunogenicity of Dato-DXd (in both the monotherapy arm and in combination with durvalumab)

Safety

To assess the safety and tolerability of Dato-DXd with or without durvalumab compared with ICT in the safety analysis set of participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.

Exploratory

To demonstrate superiority of Dato-DXd monotherapy relative to ICT by assessment of IBCFS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To demonstrate superiority of Dato-DXd in combination with durvalumab relative to ICT by assessment of IBCFS in participants with stage I to III TNBC with residual invasive disease at surgical resection following neoadjuvant therapy.
To describe participant-reported symptomatic AEs and treatment tolerability
To assess participant-reported global impression of the severity of overall cancer symptoms.
To assess participant-reported global impression of change in health status.
To assess participant-reported functioning.
To assess participant-reported health-related quality of life.
To assess fertility status

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Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

Stage IV (metastatic) TNBC.
History of prior invasive breast cancer, or evidence of recurrent disease following preoperative therapy and surgery.
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 chronic diverticulitis or previous complicated diverticulitis.
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 (including ductal carcinoma in situ) 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.
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).
Active or prior documented autoimmune or inflammatory disorders.
Clinically significant corneal disease.
Active or uncontrolled hepatitis B or C virus infection.
Known HIV infection that is not well controlled
Active tuberculosis infection.
Mean resting corrected QTcF > 470 ms regardless of gender, obtained from triplicate 12-lead ECGs performed at screening.
Uncontrolled or significant cardiac disease.
History of non-infectious ILD/pneumonitis including radiation, pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
Has severe pulmonary function compromise.
Any known active liver disease.
Grade ≥ 2 peripheral neuropathy of any aetiology.
Prior exposure to a PD-1/PD-L1 inhibitor other than pembrolizumab.
Current or prior use of immunosuppressive medication within 14 days prior to randomisation.
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.
Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors.
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.
Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

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