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

AstraZeneca

Status and phase: Enrolling; Phase 3

Conditions: Breast Cancer

Treatments: Drug: Epirubicin; Drug: Olaparib; Drug: Durvalumab; Drug: Carboplatin; Drug: Paclitaxel; Drug: Dato-DXd; Drug: Capecitabine; Drug: Doxorubicin; Drug: Pembrolizumab; Drug: Cyclophosphamide

Study type: Interventional

Funder types: Industry

Identifiers

NCT06112379

D926QC00001

2023-505928-59-00 (Registry Identifier)

Details and patient eligibility

About

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.

Full description

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

Enrollment: 1,728 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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 and aligned with protocol requirements.

Exclusion criteria

• History of any prior invasive breast malignancy
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 5 years before randomization.
• active or prior documented autoimmune or inflammatory disorders.
• 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
• Mean resting corrected QTcF interval > 470 ms obtained from ECG
• Uncontrolled or significant cardiac disease.
• History of non-infectious ILD/pneumonitis
• Has severe pulmonary function compromise
• 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.
• Concurrent use of systemic hormone replacement therapy or oral hormonal contraception

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,728 participants in 2 patient groups

Dato-DXd plus durvalumab

Experimental group

Description:

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: 1. 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); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.

Treatment:

Drug: Cyclophosphamide

Drug: Doxorubicin

Drug: Capecitabine

Drug: Paclitaxel

Drug: Dato-DXd

Drug: Carboplatin

Drug: Durvalumab

Drug: Olaparib

Drug: Epirubicin

Pembrolizumab plus chemotherapy

Active Comparator group

Description:

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.

Treatment:

Drug: Cyclophosphamide

Drug: Doxorubicin

Drug: Pembrolizumab

Drug: Capecitabine

Drug: Paclitaxel

Drug: Carboplatin

Drug: Olaparib

Drug: Epirubicin