DATOPOTAMAB DERUXTECAN for Triple-negative breast cancer (locally recurrent inoperable or metastatic)

Inclusion criteria

• {"criterion_text":"- Participant must be ≥ 18 years at the time of screening.\n- Participants with a history of previously treated neoplastic spinal cord compression or asymptomatic, stable brain metastases, who require no treatment with corticosteroids or anticonvulsants may be included in the study, if they are no longer symptomatic and have recovered from acute toxic effects of radiotherapy. A minimum of 2 weeks must have elapsed between the end of radiotherapy and Cycle 1 Day 1. A minimum of 3 days must have elapsed between the end of corticosteroid therapy for central nervous system metastatic disease and Cycle 1 Day 1\n- Adequate organ and bone marrow function within 7 days before randomisation.\n- Minimum life expectancy of 12 weeks.\n- Male or female.\n- Negative pregnancy test (serum) for women of childbearing potential.\n- Female participants must be at least 1 year post-menopausal, surgically sterile, or using at least 1 highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) Women of childbearing potential who are sexually active with a non sterilised male partner must agree to use at least 1 highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before Cycle 1 Day 1 and continue for at least 7 months after the last dose. Female participants must refrain from egg cell donation or retrieval for their own use, and breastfeeding from enrolment throughout the study and for at least 7 months after the last dose of study drug. Any non sterilised male partner of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period.\n- Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or use an acceptable method of contraception from the time of screening throughout the total duration of the study and the drug washout period (at least 6 months after the last dose of study intervention), in addition to the female partner using a highly effective contraceptive method, to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. Preservation of sperm should be considered prior to randomisation. Not engaging in heterosexual activity (sexual abstinence) for the duration of the study and drug washout period is an acceptable practice, if this is the preferred usual lifestyle of the participant. Periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.\n- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.\n- Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative.\n- Histologically or cytologically documented locally recurrent inoperable TNBC, which cannot be treated with curative intent, or metastatic TNBC.\n- No prior chemotherapy or other systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer.\n- Not a candidate for PD-1/PD-L1 inhibitor therapy.\n- At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and is suitable for accurate repeated measurements.\n- ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.\n- Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or Eribulin), based on DFI and prior taxane exposure, per investigator assessment.\n- Has had an adequate treatment washout period before Cycle 1 Day 1.\n- Written confirmation of tumour sample needs to be available prior to enrolment and tumour samples should be available prior to randomisation. All participants must have a FFPE metastatic (excluding bone) or locally recurrent inoperable tumour sample (block preferred, or a minimum of 20 freshly cut slides) available, collected ≤ 3 months prior to screening. If neither an adequate FFPE block nor the minimum of 20 slides are available from the most recent biopsy, or if a biopsy is not feasible for safety reasons, and this is clearly documented, an archival tumour specimen obtained before the diagnosis of locally recurrent inoperable or metastatic breast cancer may be submitted, pending approval by the Global Study Team."}

Exclusion criteria

• {"criterion_text":"- As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, uncontrolled hypertension, history of allogeneic organ transplant, and active bleeding diseases, ongoing or active infection, or significant cardiac or psychological conditions), 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.\n- Clinically significant corneal disease.\n- Known active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).\n- Prior exposure to any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I, or to TROP2- targeted therapy.\n- Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications except for managing AEs (inhaled steroids or intra articular steroid injections are permitted in this study).\n- Known history of severe hypersensitivity reactions to other monoclonal antibodies.\n- History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence (per investigator assessment). Exceptions include adequately resected non-melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease.\n- Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia, not yet improved to Grade ≤ 1 or baseline. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).\n- Known active or uncontrolled hepatitis B or C virus infection.\n- Known human immunodeficiency virus (HIV) infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, cluster of differentiation (CD)4+ count > 350 cells/mm3, no history of an acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications.\n- Uncontrolled hypercalcaemia: > 1.5 mmol/L (> 6 mg/dL) ionised calcium, or serum calcium (uncorrected for albumin) > 3 mmol/L (> 12 mg/dL), or corrected serum calcium > ULN, or clinically significant (symptomatic) hypercalcaemia.\n- History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening\n- Has severe pulmonary function compromise.\n- Leptomeningeal carcinomatosis."}

Primary endpoints

• {"endpoint_text":"- PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.","definition_or_measurement_approach":"PFS: time from randomisation to progression per RECIST 1.1 assessed by Blinded Independent Central Review (BICR), or death from any cause."}
• {"endpoint_text":"- OS is defined as the time from randomisation until the date of death due to any cause. The analysis will include all randomised participants, by treatment group as randomised. The measure of interest is the HR of OS","definition_or_measurement_approach":"OS: time from randomisation until date of death due to any cause; analysis includes all randomized participants by treatment group; primary measure of interest is hazard ratio (HR) of OS."}

Secondary endpoints

• {"endpoint_text":"- Objective Response Rate: Objective response rate is defined as the proportion of participants who have a confirmed CR or PR, as determined by the BICR/Investigator assessment, per RECIST 1.1.","definition_or_measurement_approach":"ORR: proportion with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by BICR or investigator assessment."}
• {"endpoint_text":"- Duration of Response: Duration of response is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1, as assessed by BICR/Investigator assessment or death due to any cause.","definition_or_measurement_approach":"DoR: time from first documented confirmed response to documented progression per RECIST 1.1 (BICR/Investigator) or death."}
• {"endpoint_text":"- Progression-Free Survival 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 (by any cause in the absence of progression), (ie, date of event or censoring – date of randomization + 1).","definition_or_measurement_approach":"Investigator-assessed PFS: time from randomization until progression per RECIST 1.1 by investigator or death."}
• {"endpoint_text":"- Disease Control Rate (DCR): Defined as best overall response of CR or PR or SD (without subsequent cancer therapy) per RECIST 1.1, as assessed by BICR/per investigator assessment and maintained for ≥ 11 weeks from randomization. DCR at 12 weeks (DCR-12) is defined as the percentage of subjects who have disease control.","definition_or_measurement_approach":"DCR: percentage with best overall response CR/PR/SD (no subsequent therapy) per RECIST 1.1 (BICR/investigator) maintained ≥11 weeks; DCR-12 is DCR at 12 weeks."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"TFST: time from randomization to start date of first subsequent anti-cancer therapy after discontinuation of randomized treatment, or death."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"TSST: time from randomization to start date of second subsequent anti-cancer therapy after discontinuation of first subsequent therapy, or death."}
• {"endpoint_text":"- 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 of the 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.","definition_or_measurement_approach":"PFS2: time from randomization to earliest of second progression (after initial progression and subsequent therapy) or death; second progression date recorded by investigator per local clinical practice."}
• {"endpoint_text":"- Clinical Outcome Assessments: TTD in a) pain (EORTC IL146), b) physical functioning (EORTC IL146), c) GHS/QoL (EORTC IL146), d) breast symptoms (EORTC IL116), e) arm symptoms (EORTC IL116).","definition_or_measurement_approach":"Clinical outcome assessments: Time to deterioration (TTD) measured using patient-reported instruments (EORTC IL146 and IL116) for specified domains."}
• {"endpoint_text":"- Pharmacokinetics","definition_or_measurement_approach":"Assessment of pharmacokinetics of Dato-DXd (sample collection and PK analyses per protocol)."}
• {"endpoint_text":"- Immunogenicity","definition_or_measurement_approach":"Assessment of immunogenicity of Dato-DXd via anti-drug antibody testing per protocol."}
• {"endpoint_text":"- Safety & tolerability","definition_or_measurement_approach":"Safety and tolerability assessed by adverse events, lab tests, vitals, and other safety assessments per protocol."}

Belgium

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

10-12-2024

Processing Time Days

230

Number Of Sites

2

Number Of Participants

20

Germany

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

13-12-2024

Processing Time Days

233

Number Of Sites

9

Number Of Participants

18

Hungary

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

14-04-2026

Processing Time Days

720

Number Of Sites

6

Number Of Participants

18

Spain

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

07-04-2026

Processing Time Days

713

Number Of Sites

10

Number Of Participants

28

Poland

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

10-03-2026

Processing Time Days

685

Number Of Sites

6

Number Of Participants

27

Italy

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

15-04-2026

Processing Time Days

721

Number Of Sites

12

Number Of Participants

42

France

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

06-05-2026

Processing Time Days

742

Number Of Sites

13

Number Of Participants

24

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden