DATOPOTAMAB DERUXTECAN for Hormone receptor-positive, HER2-negative breast cancer (inoperable or metastatic)

Inclusion criteria

• {"criterion_text":"- 1. Participant must be ≥ 18 years at the time of screening.\n- 2. Inoperable or metastatic HR+, HER2-negative breast cancer\n- 3. Progressed on and not suitable for endocrine therapy per investigator assessment and treated with 1 to 2 lines of prior chemotherapy in the inoperable/metastatic setting. Participant must have documented progression on their most recent line of chemotherapy.\n- 4. Eligible for one of the chemotherapy options listed as ICC (eribulin, capecitabine, vinorelbine, gemcitabine), per investigator assessment.\n- 5. ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to day of first dosing.\n- 6. At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1. Note: Participants with bone-only metastases are not permitted.\n- 7. Participants with a history of previously treated neoplastic spinal cord compression, or clinically inactive brain metastases, who require no treatment with corticosteroids or anticonvulsants, may be included in the study, if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of radiotherapy and study enrolment.\n- 8. Adequate organ and bone marrow function within 7 days before day of first dosing as follows: • Hemoglobin: ≥ 9.0 g/L. • Absolute neutrophil count: 1500/mm3. • Platelet count: 100000/mm3. • Total bilirubin: ≤ 1.5 × ULN if no liver metastases; or ≤ 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline. • ALT and AST: ≤ 3 × ULN for AST/ALT; however, if elevation is due to liver metastases, ≤ 5.0 × ULN is allowed. • Calculated creatinine clearance: ≥ 30 mL/min as calculated using the Cockcroft-Gault equation (using actual body weight).\n- 9. LVEF ≥ 50% by either an echocardiogram or MUGA within 28 days of first dosing.\n- 10. Has had an adequate treatment washout period before Cycle 1 Day 1, defined as: • Major surgery: ≥ 3 weeks. • Radiation therapy including palliative radiation to chest: ≥ 4 weeks (palliative radiation therapy to other areas ≥ 2 weeks). • Anticancer therapy including hormonal therapy: ≥ 3 weeks (for small molecule targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer). • Antibody-based anticancer therapy: ≥ 4 weeks with the exception of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (eg, denosumab for the treatment of bone metastases). • Immunotherapy (non-antibody-based therapy): ≥ 2 weeks or 5 times the terminal elimination T½ of the agent, whichever is longer. • Chloroquine/hydroxychloroquine: > 14 days.\n- 11. Have available a FFPE tumor sample (block preferred, or a minimum of 20 freshly cut slides), at the time of screening. Note: Sample collection in China will comply with local regulatory approval.\n- 12. Minimum life expectancy of 12 weeks at screening.\n- 13. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; (estrogens are not permitted).\n- 14. Negative pregnancy test (serum) for women of childbearing potential\n- 15. Female participants must be post-menopausal for at least 1 year surgically sterile, or using one highly effective form of birth control. Female participants must refrain from egg cell donation and breastfeeding while on study and for at least X months after the last dose of study intervention. Non-sterilized male partners of a woman of childbearing potential must use a male condom plus spermicide throughout this period.\n- 16. Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using a highly effective method of contraception from the time of screening throughout the total duration of the study and the drug washout period to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. 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; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Female partners of male participants are allowed to use HRT for contraception.\n- 17. Capable of giving signed informed consent."}

Exclusion criteria

• {"criterion_text":"- 1. Any evidence of diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.\n- 2. 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. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy, adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated.\n- 3. Persistent toxicities caused by previous anticancer therapy (excluding alopecia), not yet improved to CTCAE Version 5.0 Grade ≤ 1 or baseline. Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to first dosing and managed with SoC treatment) which the investigator deems related to previous anticancer therapy.\n- 4. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections.\n- 5. Known active or uncontrolled hepatitis B or C infection; or positive for hepatitis B or C virus based on the evaluation of results of tests for hepatitis B (HBsAg, anti-HBs, anti-HBc, or HBV DNA) or hepatitis C (HCV antibody or HCV RNA) infection at screening.\n- 6. Known HIV infection that is not well controlled.\n- 7. Uncontrolled or significant cardiac disease, including myocardial infarction or uncontrolled/unstable angina within 6 months prior to C1D1, CHF (New York Heart Association Class II to IV), uncontrolled or significant cardiac arrhythmia, or uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg).\n- 8. Investigator judgment of 1 or more of the following: • Mean resting corrected QTcF interval > 470 ms • History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. • Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.\n- 9. History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.\n- 10. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder, or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement, or prior pneumonectomy.\n- 11. Leptomeningeal carcinomatosis.\n- 12. Clinically significant corneal disease.\n- 13. Known active tuberculosis infection\n- 14. Any of the following prior anticancer therapies: o Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I - - TROP2-targeted therapy o Prior treatment with same ICC agent\n- 15. Any concurrent anticancer treatment, with the exception of bisphosphonates, denosumab, for the treatment of bone metastases.\n- 16. Concurrent use of systemic hormonal replacement therapy (eg, estrogen). However, concurrent use of hormones for non-cancer related conditions (eg, insulin for diabetes) is acceptable.\n- 17. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.\n- 18. Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment.\n- 19. ?????\n- 20. Previous treatment in the present study.\n- 21. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dosing, randomization into a prior Dato-Dxd or T-DXd (trastuzumab deruxtecan) study regardless of treatment assignment, or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.\n- 22. Participants with a known hypersensitivity to Dato-DXd, or any of the excipients of the product (including, but not limited to, polysorbate 80).\n- 23. Known history of severe hypersensitivity reactions to other monoclonal antibodies.\n- 24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).\n- 25. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.\n- 26. For women only, currently pregnant (confirmed with positive pregnancy test) or breastfeeding, or who are planning to become pregnant."}

Primary endpoints

• {"endpoint_text":"- PFS is defined as time from randomization until progression per RECIST 1.1, as assessed by BICR, or death due to any cause. The analysis will include all randomized participants as randomized regardless of whether the participant withdraws from therapy, receives another anti-cancer therapy, or clinically progresses prior to RECIST 1.1. The measure of interest is the hazard ratio of PFS.","definition_or_measurement_approach":"Time from randomization to progression per RECIST 1.1 assessed by blinded independent central review (BICR) or death; analysis includes all randomized participants as randomized; measure of interest is hazard ratio."}
• {"endpoint_text":"- OS is defined as time from randomization until the date of death due to any cause. The comparison will include all randomized participants as randomized, regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy. The measure of interest is the hazard ratio of OS","definition_or_measurement_approach":"Time from randomization to death from any cause; analysis includes all randomized participants as randomized; measure of interest is hazard ratio."}

Secondary endpoints

• {"endpoint_text":"- 1. 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":"Proportion of participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by BICR or investigator assessment."}
• {"endpoint_text":"- 2. 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":"Time from first documented confirmed response to documented progression per RECIST 1.1 by BICR/investigator, or death."}
• {"endpoint_text":"- 3. 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":"Time from randomization to progression per RECIST 1.1 as assessed by the investigator, or death; event date or censoring minus randomization date +1."}
• {"endpoint_text":"- 4. Disease Control Rate: Disease control rate at 12 weeks is defined as the percentage of participants who have a confirmed CR or PR or who have SD, per RECIST 1.1, as assessed BICR/per investigator assessment and derived from the raw tumor data for at least 11 weeks after randomization.","definition_or_measurement_approach":"Percentage of participants with confirmed CR, PR or stable disease (SD) per RECIST 1.1 at 12 weeks by BICR/investigator using tumor data for ≥11 weeks post-randomization."}
• {"endpoint_text":"- 5. 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":"Time from randomization to start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment, or death."}
• {"endpoint_text":"- 6. 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":"Time from randomization to start date of second subsequent anti-cancer therapy after discontinuation of first subsequent treatment, or death."}
• {"endpoint_text":"- 7. 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.","definition_or_measurement_approach":"Time from randomization to earliest of second progression (after initial progression and following first subsequent therapy) or death; second progression recorded by investigator in eCRF per local practice."}
• {"endpoint_text":"- 8. Clinical Outcome Assessments:The secondary PRO endpoints include:TTD in pain as measured by the pain scale from EORTC QLQ-C30, TTD in physical functioning as measured by the physical functioning scale from EORTC QLQ-C30, TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC QLQ-C30","definition_or_measurement_approach":"Time to deterioration (TTD) measured using EORTC QLQ-C30 scales: pain scale, physical functioning scale, and global health status/quality of life (GHS/QoL) scale."}
• {"endpoint_text":"- 9. Pharmacokinetics","definition_or_measurement_approach":"Assessment of PK parameters for Dato-DXd (noted in protocol: PK of 6 mg/kg IV Q3W)."}
• {"endpoint_text":"- 10. Immunogenicity","definition_or_measurement_approach":"Assessment of immunogenicity (anti-drug antibodies) for Dato-DXd."}

Belgium

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

31-07-2025

Processing Time Days

422

Number Of Sites

2

Number Of Participants

15

Hungary

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

19-06-2024

Processing Time Days

15

Number Of Sites

4

Number Of Participants

16

Spain

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

21-06-2024

Processing Time Days

17

Number Of Sites

12

Number Of Participants

66

Italy

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

04-08-2025

Processing Time Days

426

Number Of Sites

10

Number Of Participants

56

Poland

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

17-02-2025

Processing Time Days

258

Number Of Sites

8

Number Of Participants

33

Germany

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

11-02-2025

Processing Time Days

252

Number Of Sites

5

Number Of Participants

6

France

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

02-03-2026

Processing Time Days

636

Number Of Sites

1

Number Of Participants

61

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

sponsor duties code 12; contact karolina.swiech@parexel.com; phone 48695344872

Third parties

• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"sponsorDuties code 12 (contact: karolina.swiech@parexel.com)","organisation_type":"Pharmaceutical company"}