A Phase III Randomised Study to Evaluate Dato-DXd and Durvalumab for Neoadjuvant/Adjuvant Treatment of Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer

Study Overview
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Brief Summary
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This is a Phase III, 2-arm, randomised, open-label, multicentre, global study assessing the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy compared with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer.

Detailed Description
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The primary objectives of the study are to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor low/HER2-negative breast cancer, by central assessment of pCR and/or to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer, by investigator assessment of EFS

Official Title
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A Phase III, Open-label, Randomised Study of Neoadjuvant Datopotamab Deruxtecan (Dato-DXd) Plus Durvalumab Followed by Adjuvant Durvalumab With or Without Chemotherapy Versus Neoadjuvant Pembrolizumab Plus Chemotherapy Followed by Adjuvant Pembrolizumab With or Without Chemotherapy for the Treatment of Adult Patients With Previously Untreated Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer (D926QC00001; TROPION-Breast04)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Dato-DXd
* Drug: Durvalumab
* Drug: Pembrolizumab
* Drug: Doxorubicin
* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Capecitabine
* Drug: Olaparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥ 18 years, at the time of signing the ICF. Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer ECOG PS of 0 or 1 Provision of acceptable tumor sample Adequate bone marrow reserve and organ function Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Exclusion criteria: History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before randomization and of low potential risk for recurrence. Evidence of distant disease. Clinically significant corneal disease. Has active or uncontrolled hepatitis B or C virus infection. Known HIV infection that is not well controlled. Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections; or inability to rule out infections. Known to have active tuberculosis infection Resting ECG with clinically significant abnormal findings. Uncontrolled or significant cardiac disease. History of non-infectious ILD/pneumonitis Any prior or concurrent surgery, radiotherapy or systemic anticancer therapy for TNBC or hormone receptor-low/HER2-negative breast cancer For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding, or planning to become pregnant. Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention, or as dictated by local PI for SoC if longer.

Ages Eligible for Study
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Minimum Age: 18 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: Participants will be randomised in a 1:1 ratio to one of two intervention groups.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dato-DXd plus durvalumab<br>Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); Capecitabine (Q3W) for 8 cycles. | Drug: Dato-DXd<br>* Experimental drug IV infusion<br>* Other names: Datopotamab deruxtecan (Dato-DXd, DS-1062a);Drug: Durvalumab<br>* Experimental drug IV Infusion<br>* Other names: MEDI4736;Drug: Doxorubicin<br>* IV infusion Experimental/Active Comparator<br>Drug: Epirubicin<br>* IV Infusion Experimental/Active Comparator<br>Drug: Cyclophosphamide<br>* IV infusion Experimental/Active Comparator<br>Drug: Paclitaxel<br>* IV infusion Experimental/Active Comparator<br>Drug: Carboplatin<br>* IV infusion Experimental/Active Comparator<br>Drug: Capecitabine<br>* Tablet Oral route of administration Experimental/Active Comparator<br>* Other names: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord;Drug: Olaparib<br>* Tablet Oral route of administration Experimental/Active Comparator<br>* Other names: LYNPARZA®;|
| Active Comparator: Pembrolizumab plus chemotherapy<br>Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease. | Drug: Pembrolizumab<br>* IV Infusion Active comparator<br>* Other names: KEYTRUDA®;Drug: Doxorubicin<br>* IV infusion Experimental/Active Comparator<br>Drug: Epirubicin<br>* IV Infusion Experimental/Active Comparator<br>Drug: Cyclophosphamide<br>* IV infusion Experimental/Active Comparator<br>Drug: Paclitaxel<br>* IV infusion Experimental/Active Comparator<br>Drug: Carboplatin<br>* IV infusion Experimental/Active Comparator<br>Drug: Capecitabine<br>* Tablet Oral route of administration Experimental/Active Comparator<br>* Other names: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord;Drug: Olaparib<br>* Tablet Oral route of administration Experimental/Active Comparator<br>* Other names: LYNPARZA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) in the experimental vs control arms | pCR rate is defined as the proportion of participants who have no evidence by haematoxylin and eosin staining of residual invasive disease at the time of definitive surgery in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0) by blinded central evaluation. 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 difference between the pCR rates. | At the time of definitive surgery | 
| Event-free survival (EFS) in the experimental vs control arms | EFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: disease progression precluding surgery, disease recurrence (local, regional, distant, or contralateral), second primary non-breast invasive cancer (other than squamous or basal cell skin cancer), or death by any cause (in the absence of recurrence). 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 Hazard Ratio of EFS. | Date of randomization to date of the EFS event, up to 68 months after the first subject randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in the experimental vs control arms | OS is defined as the time from the date of randomisation until the 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 receives another anticancer therapy. The measure of interest will be the Hazard Ratio of OS. | Date of randomization to date of death due to any cause, up to 82 months after the first subject randomized | 
| Distant disease-free survival (DDFS) in the experimental vs control arms | DDFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: distant metastasis, occurrence of second primary non-breast invasive cancer (other than squamous or basal cell skin cancer), or death by any cause (in the absence of recurrence). 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 Hazard Ratio of DDFS. | Date of randomization to date of the DDFS event, up to 68 months after the first subject randomized | 
| Participant-reported breast and arm symptoms in the experimental vs. control arms | Breast and arm symptoms measured by the EORTC IL116. 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 is the mean between-arm difference in breast and arm symptom scores. | From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first. | 
| Participant-reported physical function in the experimental vs. control arms | Physical function measured by the PROMIS Physical Function Short Form 8c. The analysis will include all dosed participants. The measure of interest is the mean between-arm difference in physical function scores. | From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks). | 
| Participant-reported fatigue in the experimental vs. control arms | Fatigue measured by the PROMIS Fatigue Short Form 7a. The analysis will include all dosed participants. The measure of interest will be the difference on the proportions of participants reporting different levels of fatigue and mean between-arm difference in the fatigue scores. | From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks). | 
| Participant-reported Global health status/Quality of life (GHS/QoL)in the experimental vs. control arms | Global health status/Quality of life measured by EORTC IL172. 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 is the mean between-arm difference in GHS/QoL scores. | From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks). | 
| Pharmacokinetics of Dato-DXd (in combination with durvalumab) | Plasma concentrations of Dato-DXd (ug/ml ) | Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit | 
| Pharmacokinetics of Dato-DXd (in combination with durvalumab) | Plasma concentrations of total anti-TROP2 antibody (ug/ml ) | Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit | 
| Pharmacokinetics of Dato-DXd (in combination with durvalumab) | Plasma concentrations of DXd (MAAA-1181a) (ng/ml) | Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit | 
| Immunogenicity of Dato-DXd (in combination with durvalumab) | Presence of antidrug antibodies (ADAs) for Dato-DXd (confirmatory results: positive or negative, titres). | Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit | 
| Safety of Dato-DXd (in combination with durvalumab) | 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;, Dato-DXd; DS1062a;, TROP2;, TNBC;, HR low:, Datopotamab deruxtecan;, Antibody Drug Conjugate;, ADC;, neoadjuvant therapy;, adjuvant therapy;, durvalumab;, PD-L1;, immune-checkpoint inhibitor (ICI);