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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2025 → ongoing

Decision date (initial)

2024-12-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Efficacy, Safety

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

Secondary objectives 7

1. 1.To demonstrate superiority of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of OS
2. 2-5.To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of ORR/DoR/PFS (as assessed by the investigator)/CBR at 24 weeks
3. 6. To assess breast and arm symptoms, pain, physical functioning, global health status/quality of life (GHS/QoL) in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab.
4. 7-9. To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of TFST/TSST/PFS2
5. 10. To assess the pharmacokinetics of Dato-DXd in combination with durvalumab.
6. 11. To investigate the immunogenicity of Dato-DXd in combination with durvalumab.
7. 12. To assess the safety and tolerability of Dato-DXd + durvalumab as compared with ICC + pembrolizumab

Conditions and MedDRA coding

Triple-negative Breast Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Histologically or cytologically documented locally recurrent inoperable, which cannot be treated with curative intent, or metastatic TNBC, as defined by the the ASCO-CAP guidelines
2. ECOG PS 0 or 1
3. Participants are expected to provide a FFPE tumour sample collected from a locally recurrent inoperable or metastatic tumour (either de novo metastatic or recurrent metastatic, excluding bone metastases). Alternatively, an archival FFPE tumour sample can be submitted. This archival sample may come from early-stage TNBC; however, it must have been collected ≤ 3 years prior to the participant signing informed consent (screening start).
4. PD-L1 positive TNBC based on results from an appropriately validated investigational PD-L1 (22C3) assay (CPS ≥ 10) from a sponsor designated central laboratory
5. No prior chemotherapy or other systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer. Patients with recurrent disease will be eligible if they have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months have elapsed between completion of treatment with curative intent and the first documented inoperable local recurrence or distant recurrence.
6. Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
7. Measurable disease as per RECIST 1.1
8. Adequate bone marrow reserve and organ function
9. Male and female participants of childbearing potential must agree to use protocol-specified method(s) of contraception

Exclusion criteria 15

1. As judged by the investigator, severe or uncontrolled systemic diseases, uncontrolled hypertension, serious gastrointestinal conditions associated with diarrhoea, chronic diverticulitis or previous complicated diverticulitis, history of allogeneic organ transplant, and active bleeding diseases, ongoing or active infection, significant cardiac conditions, substance abuse, psychiatric illness/social situation, or psychological conditions.
2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before Cycle 1 Day 1 and of low potential risk for recurrence.
3. Neoplastic spinal cord compression or active brain metastases, leptomeningeal carcinomatosis or history of leptomeningeal carcinomatosis. Participants with a history of previously treated neoplastic spinal cord compression or treated, clinically inactive brain metastases that are no longer symptomatic, who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered from acute toxic effects of radiotherapy.
4. Uncontrolled infection requiring IV antibiotics, antivirals or antifungals
5. Active or uncontrolled hepatitis B or C virus infection
6. Known HIV infection that is not well controlled
7. Uncontrolled or significant cardiac disease
8. History of non-infectious ILD/pneumonitis (including radiation pneumonitis) that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
9. Clinically severe pulmonary function compromise.
10. Clinically significant corneal disease
11. Active or prior documented autoimmune or inflammatory disorders
12. Prior exposure to any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I and TROP2-targeted therapy
13. Any concurrent anti-cancer treatment
14. Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors or Dato-DXd
15. Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
2. 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.
3. 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 endpoints 12

1. Overall Survival (OS): OS is defined as the time from the date of randomisation until death due to any cause.
2. Objective Response Rate (ORR): Objective response rate is defined as the proportion of participants who have a CR or PR, as determined by the BICR/Investigator assessment, per RECIST 1.1.
3. Duration of Response (DoR): Duration of response 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.
4. Progression-Free Survival (PFS) by Investigator assessment: PFS by Investigator assessment will be defined as the time from the date of randomization until the date of PD per RECIST 1.1 by Investigator assessment or death due to any cause
5. Clinical benefit rate (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.
6. Clinical Outcome Assessments: The secondary PRO endpoints include: TTD in breast symptoms as measured by breast symptoms scale from EORTC IL116, TTD in arm symptoms as measured by arm symptoms scale from EORTC IL116, TTD in pain as measured by the pain scale from EORTC IL199, TTD in physical functioning as measured by the physical functioning scale from the PROMIS Short Form v2.0 – Physical Function 8c, TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172.
7. Time to First Subsequent Therapy (TFST): Time to first subsequent therapy is defined as the time from randomization until the start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment, or death due to any cause.
8. Time to Second Subsequent Therapy (TSST): Time to second subsequent therapy is defined as the time from randomization to until the start date of the second subsequent anti-cancer therapy after discontinuation of first subsequent treatment, or death due to any cause.
9. Time from randomization to second progression or death (PFS2): Time to second progression of death will be defined as the time from the randomization 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.
10. Pharmacokinetics of dato-DXd in combination with durvalumab
11. Immunogenicity of dato-DXd in combination with durvalumab
12. Safety & tolerability

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 5

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

4 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 59 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications