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

Phase 3Active Not RecruitingNCT06112379

AstraZeneca1,902 enrolled

Overview

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.

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 investigator assessment of EFS.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,902

Conditions

Breast Cancer

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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 invasive cancer (other than squamous or basal cell skin cancer), or relapse from prior malignancy, or death by any cause (in the absence of recurrence). Non-invasive breast cancers and positive margins in the surgical sample do not count as an event for EFS. EFS will be determined by the investigator 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 Hazard Ratio of EFS.

Time frame: Date of randomization to date of the EFS event, up to 93 months after the first subject randomized

Secondary Outcomes

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 or lymphovascular invasion 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.

Time frame: At the time of definitive surgery

Overall Survival (OS) in the experimental vs control arms

Key Secondary - 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.

Time frame: Date of randomization to date of death due to any cause, up to 108 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 invasive cancer (other than squamous or basal cell skin cancer), relapse from prior malignancy or death by any cause (in the absence of recurrence). DDFS will be determined by the investigator 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 Hazard Ratio of DDFS.

Time frame: Date of randomization to date of the DDFS event, up to 93 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.

Time frame: 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.

Time frame: 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.

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.

Pharmacokinetics of Dato-DXd (in combination with durvalumab)

Plasma concentrations of Dato-DXd (ug/ml )

Time frame: 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 )

Time frame: 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)

Time frame: 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).

Time frame: 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

Time frame: 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

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

Overview

Conditions

Interventions

Eligibility

Locations (283)

Outcomes

Primary Outcomes

Secondary Outcomes