A Phase III Study of Dato-DXd With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer

Phase 3

Recruiting

• Conditions: Breast Cancer
• Interventions: Drug: Dato-DXd; Drug: Paclitaxel; Drug: Nab-paclitaxel; Drug: Durvalumab; Drug: Gemcitabine; Drug: Carboplatin; Drug: Pembrolizumab

• Registration Number: NCT06103864
• Lead Sponsor: AstraZeneca

Brief Summary

This is a Phase III, randomised, open-label, 3-arm, multicentre, international study assessing the efficacy and safety of Dato-DXd with or without durvalumab compared with investigator's choice chemotherapy in combination with pembrolizumab in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.

Detailed Description

The primary objective of the study is to demonstrate superiority of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of PFS as assessed by BICR in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.

The study will be stratified based on geographic location (US/Canada/Europe vs. Dato-DXd monotherapy enrolling countries vs. rest of world), disease-free interval (DFI) history (de novo vs. prior DFI 6 to 12 months vs. prior DFI \> 12 months), and prior PD-1/PD-L1 treatment for early stage TNBC (yes vs. no).

This study aims to see if Dato-DXd with durvalumab allows patients to live longer without their breast cancer getting worse, or simply to live longer, compared to patients receiving standard of care chemotherapy and pembrolizumab. This study is also looking to see how the treatment and the breast cancer affects patients' quality of life.

Study Timeline

• Study First Submitted: 2023-10-23
• Study First Submitted QC: 2023-10-23
• Study First Posted: 2023-10-27
• Study Start: 2023-11-23
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-22
• Last Update Posted: 2024-11-25
• Primary Completion: 2026-09-01
• Study Completion: 2029-04-23

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 625

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab	Nab-paclitaxel	Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
Dato-DXd + durvalumab	Dato-DXd	Arm 1: Dato-DXd + durvalumab
Dato-DXd + durvalumab	Durvalumab	Arm 1: Dato-DXd + durvalumab
Dato-DXd	Dato-DXd	Arm 3: Dato-DXd
Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab	Paclitaxel	Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab	Gemcitabine	Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab	Carboplatin	Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab	Pembrolizumab	Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	From randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause (anticipated to be up to 33 months).	PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. The comparison will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anticancer therapy or clinically progresses prior to RECIST 1.1 progression.; However, if the participant progresses or dies immediately after 2 or more consecutive missed visits, the participant will be censored at the time of the latest evaluable assessment prior to the 2 missed visits.; The measure of interest is the HR of PFS.

Secondary Outcome Measures

Name	Time	Method
Time to deterioration (TTD) in breast and arm symptoms in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab	From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).	TTD in breast symptoms and arm symptoms as measured by the arm symptoms scale from EORTC IL116 TTD is defined as time from the date of randomisation to the date of deterioration.; Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold.
Overall Survival (OS)	From randomisation until the date of death due to any cause (anticipated to be up to 64 months).	OS is defined as the time from randomisation until the date of death due to any cause.
Objective Response Rate (ORR)	From randomisation up until progression (anticipated to be up to 33 months).	ORR is defined as the proportion of participants who have a CR or PR, as determined by the BICR/investigator assessment, per RECIST 1.1.
Duration of Response (DoR)	From the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause (anticipated to be up to 33 months).	DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause.
Progression-Free Survival (PFS) by Investigator assessment	From randomisation until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause (anticipated to be up to 33 months).	PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator, or death due to any cause.
Clinical Benefit Rate (CBR) at 24 weeks	From randomisation up until progression, or the last evaluable assessment in the absence of progression (anticipated to be up to 33 months).	CBR at 24 weeks is defined as the percentage of participants who have a CR or PR or who have SD, per RECIST 1.1, as assessed by BICR/per investigator assessment and derived from the raw tumour data for at least 23 weeks after randomisation.
Time to deterioration (TTD) in pain in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab	Time from the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).	TTD in pain as measured by the EORTC IL199.
Time to deterioration (TTD) in physical functioning in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab	From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).	TTD in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c.
Time to deterioration (TTD) in GHS/QoL in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab	From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).	TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172.
Time to First Subsequent Therapy (TFST)	From randomisation until the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause (anticipated to be up to 64 months).	TFST is defined as the time from randomisation until the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause.
Time to Second Subsequent Therapy (TSST)	From randomisation until the start date of the second subsequent anti cancer therapy after discontinuation of first subsequent treatment, or death due to any cause (anticipated to be up to 64 months).	TSST is defined as the time from randomisation until the start date of the second subsequent anticancer therapy after discontinuation of first subsequent treatment, or death due to any cause.
Progression Free Survival 2 (PFS2)	From the randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy, or death (anticipated to be up to 64 months).	PFS2 will be defined as the time from the randomisation to the earliest progression event (following the initial progression), subsequent to first subsequent therapy, or death. The date of second progression will be recorded by the investigator in the eCRF and defined according to local standard clinical practice based on radiological or clinical progression.
Pharmacokinetics of Dato-DXd in combination with durvalumab	From first dose to end of treatment (anticipated to be up to 33 months).	Concentration of Dato-DXd, total anti-TROP2 antibody, and DXd (payload) in plasma.
Immunogenicity of Dato-DXd in combination with durvalumab	From first dose to end of treatment safety follow-up (anticipated to be up to 33 months).	Presence of antidrug antibodies for Dato-DXd (confirmatory results: positive or negative, titres).
Safety and tolerability of Dato-DXd + durvalumab as compared with ICC + pembrolizumab	From first dose to end of treatment safety follow-up (anticipated to be up to 33 months).	Safety and tolerability will be evaluated in the safety population in terms of AEs.

Trial Locations

Locations (1)

Research Site; 🇻🇳 Vinh, Vietnam