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
- Conditions
- Triple-negative Breast Cancer
- Registration Number
- 2023-503675-24-00
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing, recruiting
- Sex
- Not specified
- Target Recruitment
- 34
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
ECOG PS 0 or 1
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). If no such sample is available, 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).
PD-L1 positive TNBC based on results from an appropriately validated investigational PD-L1 (22C3) assay (CPS ≥ 10) from a sponsor designated central laboratory
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.
Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
Measurable disease as per RECIST 1.1
Adequate bone marrow reserve and organ function
Male and female participants of childbearing potential must agree to use protocol-specified method(s) of contraception
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.
Clinically significant corneal disease
Active or prior documented autoimmune or inflammatory disorders
Prior exposure to any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I and TROP2-targeted therapy
Any concurrent anti-cancer treatment
Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors or Dato-DXd
Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant
History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before Cycle 1 Day 1 and of low potential risk for recurrence
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.
Uncontrolled infection requiring IV antibiotics, antivirals or antifungals
Active or uncontrolled hepatitis B or C virus infection
Known HIV infection that is not well controlled
Uncontrolled or significant cardiac disease
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
Severe pulmonary function compromise
Study & Design
- Study Type
- Not specified
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. 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. 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. 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 Overall Survival (OS): OS is defined as the time from the date of randomisation until death due to any cause. Overall Survival (OS): OS is defined as the time from the date of randomisation until death due to any cause.
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. 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.
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. 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.
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 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
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. 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.
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. 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.
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. 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.
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. 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.
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. 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.
Pharmacokinetics of dato-DXd in combination with durvalumab Pharmacokinetics of dato-DXd in combination with durvalumab
Immunogenicity of dato-DXd in combination with durvalumab Immunogenicity of dato-DXd in combination with durvalumab
Safety & tolerability Safety & tolerability
Trial Locations
- Locations (25)
Istituto Europeo Di Oncologia S.r.l.
🇮🇹Milan, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Rome, Italy
Istituto Oncologico Veneto
🇮🇹Padova, Italy
Azienda USL Toscana Centro
🇮🇹Empoli, Italy
Azienda Ospedaliero Universitaria Di Modena
🇮🇹Modena, Italy
IRCCS Istituto Nazionale Tumori Fondazione Pascale
🇮🇹Naples, Italy
Humanitas Mirasole S.p.A.
🇮🇹Rozzano, Italy
Azienda USL IRCCS Di Reggio Emilia
🇮🇹Reggio Emilia, Italy
Ospedale San Raffaele S.r.l.
🇮🇹Milan, Italy
Azienda Socio Sanitaria Territoriale Papa Giovanni Xxiii
🇮🇹Bergamo, Italy
Scroll for more (15 remaining)Istituto Europeo Di Oncologia S.r.l.🇮🇹Milan, ItalyGiuseppe CuriglianoSite contact+390257489599giuseppe.curigliano@ieo.it