| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage I-III triple-negative breast cancer with residual invasive disease after neoadjuvant therapy. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
1. To demonstrate superiority of Dato-DXd + durvalumab relative to ICT by
a) DDFS, b) OS.
2. To demonstrate superiority of Dato-DXd relative to ICT by iDFS.
3. To assess efficacy of Dato-DXd relative to ICT by
a)DDFS, b) OS.
4. To assess efficacy of Dato-DXd relative to ICT by
a) iDFS, b) DDFS, c) OS.
5.To assess efficacy of Dato-DXd + durvalumab relative Dato-DXd by
a) iDFS, b) DDFS.
6.To assess by TTD and score levels of participant-reported a) physical function, b) QHS/QoL with Dato-DXd +/- durvalumab vs ICT.
7.To assess patient-reported fatigue Dato-DXd +/- durvalumab vs ICT.
8.To assess the a) pharmacokinetics and b) immunogenicity of Dato-Dxd.
9.To assess safety and tolerability of Dato-DXd +/- durvalumab vs ICT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥ 18 years at the time of screening; Male or female;
2. Histologically confirmed invasive TNBC.
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 taxane with or without carboplatin, with or without pembrolizumab.
5. No evidence of locoregional or distance relapse
6. Surgical removal of all clinically evident disease in the breast and lymph nodes
7. FFPE tumor sample from residual invasive disease at surgery
8. No adjuvant systemic therapy. Radiotherapy (if indicated) delivered before start of study treatment
9. No more than 6 weeks between completion of post-operative radiation therapy and randomization. If no post-operative radiation therapy, no more than 16 weeks between the date of breast surgery and randomization
10. Eligible for one of the therapy options listed as ICT
11. No known germline BRCA1 or BRCA 2 mutation
12. Adequate organ and bone marrow function; LVEF ≥ 50% by echocardiogram or MUGA; ECOG 0 or 1 |
|
| E.4 | Principal 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. Prior anticancer therapy with topoisomerase I ADC, TROP2-targeted therapy (e.g., Trodelvy), participated in clinical studies with T-DXd
4. Prior exposure to a PD-1/PD-L1 inhibitor other than pembrolizumab
5. 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; infections; active or uncontrolled HBC or HCV; HIV; active TB
6. Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to Grade ≤1
7. History of ILD or severe pulmonary function compromise
8. Clinically significant corneal disease
9. Any known active or prior documented autoimmune or inflammatory disorders
10. Any known active liver disease
11. Uncontrolled or significant cardiac disease
12. Grade ≥2 peripheral neuropathy of any etiology
13. History of severe hypersensitivity to either drug substances or inactive ingredients of Dato-DXd or history of hypersensitivity to PD-1/PD-L1 inhibitors or capecitabine |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Invasive disease-free survival (iDFS) is defined as time from randomization until date of first occurrence of one of the following events: ipsilateral invasive breast tumor (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 randomized participants, as randomized, regardless of whether the participant withdraws from randomized therapy or receives another anticancer therapy.
The measure of interest will be the HR of iDFS for Dato-DXd + durvalumab vs ICT. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For iDFS: from randomization until recurrence as assessed by investigator or death due to any cause (anticipated to be up to 57 months after first subject in) |
|
| E.5.2 | Secondary end point(s) |
1. Distant disease free survival (DDFS): 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 of DDFS for Dato-DXd + durvalumab vs. ICT.
2. DDFS for Dato-DXd vs ICT
3. DDFS for Dato-DXd + durvalumab vs Dato-DXd
4. Overall Survival (OS): 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. Measure of interest will be the HR of OS for Dato-DXd + durvalumab vs ICT
5. OS for Dato-DXd vs ICT
6. iDFS for Dato-DXd vs ICT
7. iDFS for Dato-DXd + durvalumab vs ICT
8. Clinical Outcome Assessments (PRO endpoints): Time to Deterioration (TTD) and actual scores: in physical function as measured by the PROMIS Physical Function Short Form 8c and GHS/QoL as measured by the GHS/QoL scale from the EORTC IL172. The measure of interest is the HR of TTD and physical function and GHS/QoL scores for Dato-DXd +/-
durvalumab vs ICT.
9. Fatigue as measured by PROMIS Fatigue Short Form 7a The measure of interest is the proportion of participants experiencing different levels of fatigue and actual scores at 3, 6, 12 months for Dato-DXd +/- durvalumab vs ICT.
10. Pharmacokinetics of Dato-DXd
11. Immunogenicity of Dato-DXd
12. Safety and tolerability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3, 6, 7,8 : Randomization to event, anticipated to be up to 57 months after first subject in.
4, 5: Randomization to date of death, due to any cause, up to 87 months after first subject in.
9. Randomization to 12 months after randomization.
10. Day 1 of cycles 1,2,4,6,8.
11. Day 1 of cycles 1,2,4,6,8; EoT and 30 days after EoT.
12. Randomization to final safety follow up visit 90 days after EoT. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 105 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Taiwan |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Greece |
| Italy |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
A participant is considered to have completed the study if they have completed all phases of the study, including the last visit and undergone determination of OS.
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at undue risk because of clinically significant findings.
The end of the study is defined as the date of the last visit of the last participant in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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