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

JRCT ID: jRCT2031230723

Registered date:20/03/2024

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Breast Cancer
• Date of first enrollment: 01/04/2024
• Target sample size: 1728
• Countries of recruitment: Korea,Japan,Switzerland,Japan,Canada,Japan,Taiwan,Japan,Australia,Japan,United Kingdom,Japan,Turkey,Japan,India,Japan,Hong Kong,Japan,Malaysia,Japan,Singapore,Japan,Bulgaria,Japan,United States,Japan,Italy,Japan,Poland,Japan,Belgium,Japan,France,Japan,Thailand,Japan,Austria,Japan,Germany,Japan,Spain,Japan,Hungary,Japan,Brazil,Japan,China,Japan,Vietnam,Japan
• Study type: Interventional

Intervention(s)

- Experimental arm: Dato-DXd plus durvalumab neoadjuvant therapy followed by durvalumab-based adjuvant therapy
- Control arm: Pembrolizumab plus chemotherapy neoadjuvant therapy followed by pembrolizumab-based adjuvant therapy

Outcome(s)

• Primary Outcome: central assessment of pCR, investigator assessment of EFS

Secondary Outcome

- Overall Survival (OS)
- Distant Disease-Free Survival (DDFS)
- To assess participant-reported breast and arm symptoms in participants
- To assess participan-reported physical function in participants
- To assess participant-reported fatigue in participants
- To assess participant-reported GHS/QoL in participants
- Pharmacokinetics (PK)
- To investigate the immunogenicity

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Participant must be >= 18 years at the time of signing the ICF.
2. 2. Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer defined as the following combined primary tumour (T) and regional lymph node (N) anatomical staging per AJCC for breast cancer staging system edition 8 (Hortobagyi et al 2017) as assessed by the investigator based on radiological and/or clinical assessment (T1b or T1c, N1 to N2; T2, N0 to N2; T3, N0 to N2; T4a d, N0 to N2).
Note: bilateral tumour (ie, synchronous cancers in both breasts) and/or multifocal primary tumour is allowed, as well as inflammatory breast cancer, and the tumour with the most advanced T stage should be used to assess the eligibility. If multifocal/multicentric disease, TNBC or hormone receptor-low/HER2-negative breast cancer needs to be confirmed for each focus. Synchronous contralateral DCIS will be allowed if ipsilateral breast cancer meets the criteria. For participants presenting with clinically positive axillary nodes (palpable or suspicious on imaging), a nodal biopsy (core-needle biopsy or fine needle aspiration acceptable) must be obtained prior to randomisation to confirm node positive at baseline.
TNBC or hormone receptor-low/HER2-negative breast cancer is defined as:
(a) Negative for ER with < 1% of tumour cells positive for ER on IHC and negative for PR with < 1% of tumour cells positive for PR on IHC, or hormone receptor-low (ER 1% to < 10% and/or PR 1% to < 10%; neither hormone receptor may be >= 10%); and
(b) Negative for HER2 with 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence of amplification on ISH (Allison et al 2020; Wolff et al 2018; Yoder et al 2022).
3. ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to baseline at screening and prior to randomisation.
4. Provision of acceptable tumour sample prior to randomisation as defined in the Laboratory Manual and summarised in Section 8.8.
5. Adequate bone marrow reserve and organ function within 7 days before randomisation.

Exclude criteria

1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active infection, serious chronic gastrointestinal conditions associated with diarrhoea, active bleeding diseases and significant cardiac or psychological, psychiatric illness/social situations, chronic diverticulitis or previous complicated diverticulitis), history of allogenic organ transplant, and/or substance abuse which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
2. Refractory nausea and vomiting, inability to swallow a formulated product, or previous significant bowel resection, that would preclude adequate absorption, distribution, metabolism, or excretion of capecitabine or olaparib.
3. History of another primary malignancy
(a) Any prior invasive breast malignancy.
Note: for synchronous tumours with contralateral DCIS, curative surgery for DCIS may be performed as part of the surgery after the neoadjuvant phase.
(b) Another primary malignancy except for non-breast malignancy treated with curative intent with no known active disease within 5 years before randomisation. Patients with history of malignancy should have completed all curative intent anticancer therapy including but not limited to surgery, radiotherapy, adjuvant or neoadjuvant therapy (eg, chemotherapy, hormone therapy, targeted therapy, or immunotherapy) more than 5 years before randomisation. Exceptions include adequately resected non melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) curatively treated in situ disease, including curatively treated DCIS disease.
4. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and autoimmune myocarditis. The following are exceptions to this criterion:
(a) Participants with vitiligo or alopecia.
(b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Participants without active disease in the last 5 years may be included but only after consultation with the study clinical lead.
(e) Participants with coeliac disease controlled by diet alone.
5. Evidence of distant disease.
Note: Participants must have evidence of M0 disease based on the assessments from their initial diagnosis. In the event of suspected regional or distant metastases during screening, participants should be thoroughly evaluated as clinically indicated, and those with metastatic disease should be excluded. Imaging (eg, CT, MRI, bone scan) will be performed at the discretion of the investigator, as per the local institution's SoC and in alignment with AJCC guidelines (Hortobagyi et al 2017).
6. Clinically significant corneal disease.

Related Information

• Primary Sponsor: Inoguchi Akihiro
• Secondary Sponsor: AstraZeneca
• Secondary ID(s): NCT06112379