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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Dato-DXd
* Drug: Durvalumab
* Drug: Capecitabine
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dato-DXd in combination with Durvalumab<br>Arm 1: Dato-DXd 6 mg/kg IV Q3W x 8 cycles + Durvalumab 1120 mg IV Q3W x 9 cycles | Drug: Dato-DXd<br>* Experimental drug. Provided in 100mg vials. IV infusion<br>* Other names: Datopotamab deruxtecan (Dato-DXd, DS-1062a);Drug: Durvalumab<br>* Experimental drug. Provided in 50mg vials. IV infusion<br>* Other names: MEDI4736;|
| Experimental: Dato-DXd<br>Arm 2: Dato-DXd 6 mg/kg IV Q3W x 8 cycles | Drug: Dato-DXd<br>* Experimental drug. Provided in 100mg vials. IV infusion<br>* Other names: Datopotamab deruxtecan (Dato-DXd, DS-1062a);|
| Active Comparator: Investigators Choice Therapy<br>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. | Drug: Capecitabine<br>* Active Comparator. Tablet. Oral route of administration<br>* Other names: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord;Drug: Pembrolizumab<br>* Active Comparator. Provided in 100mg vials. IV infusion<br>* Other names: KEYTRUDA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive disease-free survival (iDFS) for Dato-DXd + durvalumab vs. ICT | 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. | From randomisation to date of the event, up to 57 months from first subject in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distant disease-free survival (DDFS) for Dato-DXd + durvalumab vs ICT | DDFS is defined as time from randomisation 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 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 DDFS for Dato-DXd + durvalumab vs ICT. | From randomisation to date of the event, up to 57 months from first subject in | 
| DDFS for Dato-DXd vs ICT | DDFS is defined as time from randomisation 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 (hazard ratio) of DDFS for Dato-DXd vs ICT. | From randomisation to date of the event, up to 57 months from first subject in | 
| DDFS for Dato-DXd + durvalumab vs Dato-DXd | DDFS is defined as time from randomisation 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 (hazard ratio) of DDFS for Dato-DXd + durvalumab vs Dato-DXd. | From randomisation to date of the event, up 57 months from first subject in | 
| Overall Survival (OS) for Dato-DXd + durvalumab vs ICT | OS is defined as time from randomisation 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. | From randomisation to date of death, due to any cause, up to 87 months from first subject in | 
| OS for Dato-DXd vs ICT | OS is defined as time from randomisation until date of death due to any cause. The measure of interest will be the HR (hazard ratio) of OS for Dato-DXd vs ICT. | From randomisation to date of death, due to any cause, up to 87 months from first subject in | 
| iDFS for Dato-DXd vs ICT | 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 vs ICT. | From randomisation to date of the event, up to 57 months from first subject in | 
| iDFS for Dato-DXd + durvalumab vs Dato-DXd | 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 (hazard ratio) of iDFS for Dato-DXd + durvalumab vs Dato-DXd. | From randomisation to date of the event, up to 57 months from first subject in | 
| Participant-reported physical function in participants treated with Dato-DXd with or without durvalumab compared with ICT | Time to Deterioration (TTD) and actual scores 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 and mean between-arm difference in physical function for Dato-DXd with or without durvalumab compared with ICT. | From randomisation to date of the deterioration, up to 36 months after randomisation | 
| Participant-reported in GHS/QoL in participants treated with Dato-DXd with or without durvalumab compared with ICT | Time to Deterioration (TTD) and actual scores 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 and mean between-arm difference in GHS/QoL for Dato-DXd with or without durvalumab compared with ICT. | From randomisation to date of the deterioration, up to 36 months after randomisation | 
| Participant-reported fatigue in participants treated with Dato-DXd with or without durvalumab compared with ICT | 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. | From randomisation to 24 months after randomisation | 
| Pharmacokinetics of Dato-DXd | Concentration of Dato- DXd, total anti-TROP2 antibody, and MAAA-1181 in plasma. | Day 1 of cycles 1,2,4,6,8 (Each cycle is 21 days) | 
| Immunogenicity of Dato-DXd | Presence of ADAs for Dato-DXd (confirmatory results: positive or negative; titres). | 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) | 
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Safety and tolerability will be evaluated in terms of AEs (graded by CTCAE version 5.0). | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, TNBC, Triple-negative, Adjuvant, Datopotamab Deruxtecan, Dato-DXd, DS1062a, Antibody Drug Conjugate, ADC, TROP2, Durvalumab